PROGRESS REPORT

Fatty Liver: Biochemical and Clinical Considerations Anastacio M. Hoyumpa, Jr., MD, Harry L. Greene, MD, G. Dewey Dunn, MD, and Steven Schenker, MD Sources of Hepatic Fatty Acids The three main sources of hepatic fatty acids available for triglyceride formation are dietary fat, adipose tissue, and fatty acid synthesis within the liver. D i e t a r y Fat. Ingested fats consist primarily of triglycerides composed of long-chain fatty acids. These are hydrolyzed in the small intestinal lumen to monoglycerides and fatty acids which are then absorbed as such, resynthesized to triglycerides in the intestinal mucosa, and released into lymph as chylomicrons (packets of cholesterol, phosphoiipid, and triglyceride added to a r T h e chylomicrons enter the blood stream and are dispersed to all NORMAL HEPATIC LIPID parts of the body, including the liver. MediumMETABOLISM chain triglycerides are hydrolyzed, and the meTriglyceride buildup in the liver ensues when dium-chain fatty acids are absorbed as such and the rate of triglyceride formation exceeds its carried directly to the liver via portal blood. subsequent disposition from the liver. The forChylomicron triglyceride probably must always mation of triglyceride depends on the influx of be hydrolyzed to fatty acids before entering the fatty acids into the liver or synthesis of fatty hepatocyte. Most of the hydrolysis carried out acids in the liver and their subsequent esterifiby lipoprotein lipase takes place in adipose tiscation. Removal of fat from the liver is carried sue with some fatty acids bound to plasma albuout by its secretion as very-low-density lipmin being returned to the liver (9). Other trioprotein (VLDL) or its oxidation to CO2, H20, and/or ketones. T h e normal pathways of lipid glycerides (25%) are hydrolyzed at the liver plasma membrane (Figure 1A). metabolism (1-8) to be discussed are designated A d i p o s e T i s s u e Fat. During fasting adipose in Figure 1 by the letters A through E, and the tissue serves as an important reservoir of fatty presumed primary abnormalities in various acids and is especially vital as a source of energy types of fatty liver, insofar as they are known, (Figure 1 B). T h e mobilization of adipose fatty are given by the numbers. acids is influenced by hormonal, neural, and From the Division of Gastroenterology, Vanderbih Uni- pharmacologic regulatory mechanisms, some of versity Medical School and Veterans Administration Hoswhich are mediated by cyclic AMP. Corticopital, Nashville, Tennessee. Research supported by NIH Grant 5 RO 1 AA 00267- steroids and s y m p a t h e t i c s t i m u l a t i o n in05. crease (10) and certain drugs (ie, nicotinic acid, Address for reprint requests: Dr. Anastacio M. Hoyumpa, Jr., Vanderbih University Medical School, clofibrate (Atromid S)(11) may decrease the rate of release of peripheral-depot fatty acids. Nashville, Tennessee 37203.

Fatty liver may be defined as an acctJmulation of lipid, consisting principally of triglycerides in most cases, which exceeds 5~ of the liver weight. T h e clinical importance of excess fat varies with its cause and quantity. In some instances (ie, obesity) it may be of little consequence, whereas in others (ie, fatty liver of pregnancy) it may lead to hepatic failure and death. The aim of this brief review is to summarize the main clinical and biochemical features of the principal conditions associated with significant fatty infiltration of the liver as the primary pathologic finding.

1142

Digestive Diseases, Vol. 20, No. 12 (December 1975)

FATTY LIVER EXTRACELLULAR FLUID

HEPATOCYTE

D

C

7 ~.GLUCOSE J

,-~ ~

v

r2~

FATTY~AC n ~ TTYACJD BIOSYNTHESIS

OSE T SSUE

I

M

.

*

i

O\ o ~

1 )

~ ~

\

|174

I'

I /

l

I IX"

~

J

KETONE BODIES~o OXIDATION

\

(SLUR]

/~ / 9

.~. T

FFA+O'CE,OL--~ ~--~M (DIETARY FAT)

ISERI

I/ g[

a GLYCEROPHOSPHATE

/, ~E P~

Lc.u

)

CARBOHYDRATE '

LIPOLYSIS

1

L I

MITOCNONDRION

Fig 1. Lipid metabolism in relation to fatty liver. The normal pathways of lipid metabolism are designated by the letters A through E and the presumed primary abnormalities in the different types of fatty liver are shown by the numbers 1 to 8 (1, alcohol induced; 2, kwashiorkor; 3, obesity; 4, postjejunal bypass; 5, diabetes; 6, idiopathic fatty liver of pregnancy; 7, tetracycline; 8, Reye's syndrome). VLDL, very-low-density lipoprotein; FFA, free fatty acid; TG, triglyceride; CE, cholesterol ester; PL, phospholipid. aGP, a-glycerophosphate; SER, smooth endoplasmic reticulum; RER, rough endoplasmic reticulum; TCA cycle, tricarboxylic acid cycle; ATP, adenosine triphosphate.

The mobilized fatty acids are transported to the liver bound to plasma albumin, are taken up by the hepatocyte, and may be initially stored in the liver bound to high-affinity acceptor proteins (12). Hepatic Fatty Acid Synthesis. When there is excessive dietary intake of carbohydrate, the liver can synthesize fatty acids with the main product being palmitate (C 16:0) (Figure 1C). The major site of synthesis of fatty acids inDigestive Diseases, Vol. 20, No. 12 (December 1975)

volves an aggregate of enzymes located in the cytoplasm of the cell. However, the primary source of acetyl-CoA, which is the main precursor of fatty acids, is in the mitochondria and the mitochondrial membranes are rather impermeable to acetyl-CoA. It has been shown that pyruvate produced from glucose by the glycolytic pathway diffuses into the mitochondria where it is subject to oxidative decarboxylation by the "pyruvate dehydrogenase complex" to 1143

HOYUMPA ET AL

form acetyl-CoA. A product of acetyl-CoA (citrate) may then diffuse out of the mitochondria where acetyl-CoA is formed and lipogenesis occurs. The rate-limiting reaction in the lipogenic pathway is at the acetyl-CoA carboxylase step with various factors such as acyl-CoA molecules regulating the activity of this enzyme. As longchain acyl-CoA molecules accumulate in the hepatocyte resulting from lipogenesis, these can be esterified to form triglyceride.

Disposition of Hepatic Fatty Acids

Fatty acids within the liver are either esterifled to triglycerides, phospholipids and cholesteryl esters or directly oxidized (Figure 1). Fatty Acid Esterification and V L D L Secretion. Most of the fatty acids within the liver are esterified to triglycerides within the smooth endoplasmic reticulum (SER). The triglyceride is then packaged with fl-apoprotein (synthesized by the rough endoplasmic reticulum, RER) as well as phospholipids and cholesterol (13, 14). The precise mechanism by which the apoprotein and various lipids interact to form the lipoprotein is not known, but it has been postulated that ~-apoprotein is inserted into the RER membrane, sequestering a bilayer domain as an initial step in V L D L formation (15). This phospholipid-protein complex then moves into the SER which contains enzymes for triglyceride synthesis. Surface polar lipids (phosphatidic acid and diglycerides) are then converted to core triglyceride resulting in triglyceride spheres. Carbohydrates are added to apoproteins from the RER to the Golgi system where the complete V L D L particles are formed and transported to the cell surface in secretory vescicles before being extruded into the blood stream by a poorly understood mechanism. Decreased removal of hepatic triglyceride (as the VLDL) thus can result from impaired synthesis of the V L D L apoprotein, improper packaging of the particle, or impaired secretion of the V L D L from the liver into the circulation (Figure 1). 1144

Fatty Acid O x i d a t i o n . The other important mechanism for removal of hepatic fat is fatty acid oxidation. The balance between oxidation or esterification of hepatic fatty acids is influenced by the hormonal state and the availability of a-glycerophosphate. Insulin depresses cyclic AMP activation of lipolysis in the liver, thus promoting net fatty acid esterification. When there is increased availability of a-glycerophosphate, fatty acids will be esterified to form triglyceride. Fatty acids are normally oxidized in the mitochondria by B-oxidation, ie, removal of 2 carbon atoms at a time from the carboxyl end of the fatty acid molecule. For long-chain fatty acids, the process depends on carnitine acyhransferase within the mitochondrial membrane which facilitates the transfer of these substances to the mitochondrial oxidizing machinery. Once inside the mitochondria, fatty acids are "energized" via ATP to "active fatty acids" or acyl-CoA via the enzyme, thiokinase. The subsequent catabolic pathway utilizes thiolase as the enzyme and NAD as coenzyme and gradually degrades the fatty acids by removal of 2 carbon segments to acetyl-CoA which is oxidized to CO 2 and water within the mitochondria via the citric acid cycle. When the rate of fatty acid oxidation is high (ie, diabetes mellitus and starvation), the C 2 units formed by B-oxidation may condense by a reversal of the thiolase reaction to form acetoacetyl-CoA. This in turn may be converted to acetoacetate, which diffuses into the circulation and undergoes spontaneous decarboxylation to acetone. Acetoacetate may also be converted in the liver to ~-hydroxybutyrate which also passes into the blood stream. These three substances, acetoacetate, acetone, and /3-hydroxybutyrate, are known as ketone bodies and must be oxidized by extrahepatic tissues. It is evident from this brief summary of certain aspects of normal hepatic fat metabolism that fatty liver may result from any combination of (1) increased delivery of fatty acids to the liver, (2) increased synthesis of fatty acids within the liver, (3) decreased oxidation of hepatic fatty Digestive Diseases, Vol. 20, No. 12 (December 1975)

FATTY LIVER

acids, and (4) impaired removal of hepatic triglyceride as the VLDL particles.

Table 1. Liver "Function" Tests in 83 Patients with Alcohol-Induced Fatty Liver (22)

Test DISORDERS

ASSOCIATED

WITH

FATTY LIVER E t h a n o l - I n d u c e d Fatty Liver

In the United States excessive alcohol ingestion appears to be the most common cause of fatty liver accompanied by clinical and/or biochemical evidence of hepatic dysfunction (16). The excess fat is present primarily in the form of triglyceride and varies from mild to extensive. The degree of steatosis, however, does not correlate well with the degree of alcohol intake in most reports (16, 17), probably because the history of alcohol intake (both as to quantity and duration) is notoriously unreliable, dietary intake varies extensively among such patients, liver biopsy for assessment of fat content is obtained at different times following cessation of alcohol intake, and histologic quantitation of fatty liver reflects only very grossly the actual hepatic fat content when assayed chemically (18). Despite these qualifications, it is now well established in both experimental animals and in man that alcohol, even in amounts insufficient to reach blood alcohol levels considered as legal inebriation, may induce a fatty liver. This has been demonstrated experimentally despite provision of an adequate or even high protein diet and multivitamins, indicating that ethanol p e r se is responsible for this finding (19, 20). Diet, however, clearly may exert a modifying influence on the degree and composition of hepatic fat accumulation which accompanies alcoholism. Thus, with more than 25% of the dietary calories in the form of fat, increasing the fat intake results in greater hepatic fat content which then reflects the dietary lipid composition (21). The role of protein malnutrition, which often accompanies alcoholism, in aggravating hepatic damage in such individuals is not clearly defined. In children, protein malnutrition leads to steatosis. One might anticDigestive Diseases, Vol. 20, No. 12 (December 1975)

BSP

Abnormal

Range of

(%)

abnormality

75.9

5-32%

47.9

4-11.3 BU

Alkaline phosphatase

Bilirubin

39.1

1.0-2.6

SGOT

34.6 27.0 25.6 22.9 9.5

40-210 units 250-470 mg/100 ml 3.6-2.2 g/100 m~ 3.0-4.9 g/100 ml 40-57 units

Cholesterol Albumin

Globulins SGPT Cephalin flocculation Thymol turbidity

8.4 6.1

3-4+ 4-8 units

ipate, therefore, that this will also occur in adults, compounding the effect of alcohol, but this problem requires further study. There are surprisingly few published reports on the clinical and laboratory features of ethanol-induced fatty liver wherein the presence of concomitant alcoholic hepatitis and/or cirrhosis has been fully excluded by percutaneous liver biopsy. In the best available study, which also contains some patients with nonalcoholic fatty liver, hepatomegaly occurred in 75% of patients and abdominal pain or tenderness in 18%, reflecting primarily distention of the liver by fat (17). Also, consistent with the relative acuteness and mildness of the disease, the incidence of jaundice (15%), spider angiomata (8%), splenomegaly (4%), and ascites (12%) was low. On the other hand 21~ of the patients had peripheral neuropathy, and 59% had evidence of other vitamin deficiency. As shown in Table 1 (22), the liver "function" tests in this disorder likewise are usually not seriously deranged (ie, mild hyperbilirubinemia). On occasion, however, with concomitant hemolysis or even without gross evidence of it, jaundice can be severe. It is generally agreed that the BSP retention test is the most sensitive routine test for detecting mild hepatic dysfunction in nonicterie patients with ethanol-induced fatty liver (22). The usefulness 1145

HOYUMPA ET AL

of the recently described plasma bile and clearance to detect mild forms of this disorder requires future evaluation. Histologically the fat varies in amount and is randomly distributed in the hepatic lobule. Occasionally in early lesions the fat may appear as fine droplets, but more commonly the cytoplasm of the hepatocyte is ballooned and the nucleus displaced peripherally. In severe fatty change rupture of adjacent fatty hepatocytes gives rise to fatty cysts which occasionally may be surrounded by mononuclear leukocytes forming the so-called lipogranuloma (23-25). In general, the extent of steatosis present histologically does not correlate well with the degree of abnormality in liver function tests, although mild fatty liver (2+ or less) is accompanied often by less-deranged liver function tests (22). By clinical criteria alone, however, alcoholic fatty liver cannot be differentiated from alcoholic hepatitis or cirrhosis in the individual patient with any degree of assurance. Fatty liver, of course, may, and often does, accompany alcoholic hepatitis and/or cirrhosis. In the presence of the latter conditions, which are beyond the scope of this discussion, the clinical and laboratory abnormalities are usually accentuated. The mechanism of ethanol-induced fatty liver has been the object of much investigation. A consensus has developed lately that in man the primary abnormality which leads to triglyceride accumulation following alcohol is impaired oxidation of fatty acids (20, 26) (Figure 1). This may be accompanied during explosive binges, and with concomitant starvation, by influx of fatty acids from peripheral fat depots to the liver, by increased hepatic fatty acid synthesis and elongation resulting from an increased N A D H / NAD ratio accompanying alcohol metabolism, and perhaps by decreased output of triglyceride from the liver as the VLDL at high alcohol levels (26). Each of these mechanisms may contribute to the development of a fatty liver following alcohol, but their importance and even their existence has been questioned by some investigators, while the primacy of impaired fatty acid 1146

oxidation has gained increasing credibility. Oxidation of fatty acids is carried out in the mitochondria via the citric acid cycle, and it has been clearly demonstrated that this metabolic sequence is inhibited following alcohol administration. The precise site of impairment in citric acid activity is still under investigation, but the primary mechanism appears to be a shift in the redox potential (increased N A D H / N A D ratio) (20, 26). This in turn has been reported to inhibit the citric acid cycle at the citrate synthase and isocitrate dehydrogenase steps as well as at a-ketoglutarate oxidation. Furthermore, because of decreased fatty acid oxidation, the acyl-CoA derivatives of fatty acids increase and eventually interfere with the translocation of ADP into mitochondria, with subsequent decrease in ATP synthesis (27). After chronic alcohol administration decreased fatty acid oxidation persists, even after cessation of alcohol intake, suggesting also a more persistent alteration in mitochondrial function independent of ongoing alcohol metabolism. As evidence of hepatic mitochondrial damage by alcohol, these organelles show abnormal morphology, increased fragility and permeability, and a variety of functional aberrations (5, 20, 26). The prognosis of alcoholic fatty liver (in the absence of alcoholic hepatitis or cirrhosis) is generally good, and the disease is self-limited provided alcohol intake is stopped and an adequate diet is ingested. On the other hand, patients with the fatty liver do exhibit a variety of ultrastructural lesions consisting of mitochondrial changes, disruption of the rough endoplasmic reticulum, and other nonspecific organellar alterations, whose overall functional significance is still uncertain (28). Furthermore, in a recent preliminary report patients with alcoholic fatty liver did show a twofold increase in hepatic protocollagen proline hydroxylase activity (presumably an index of collagen turnover), suggesting that propensity for deposition of fibrous tissue may already begin at the fatty liver stage (29). This is corroborated by the observations that fatty liver in alcoholics is associated Digestive Diseases, Vol. 20, No. 12 (December 1975)

FATTY LIVER

with an increase in uptake of proline and hydroxyproline into the salt-soluble (but not the insoluble) fraction of liver collagen (30). D N A synthesis in such liver, however, is normal. In rats and baboons fed alcohol and developing a fatty liver, there is also evidence of increased collagen synthesis (31). These composite data may be tentatively interpreted as indicating that fatty liver alone is accompanied by some increase in collagen synthesis but that this is a mild and reversible process and that progressive deposition of fibrous tissue depends on subsequent hepatic necrosis and inflammation (ie, alcoholic hepatitis). Finally, sudden death has been reported in alcoholics characterized at autopsy only by fatty liver (32). The cause of these deaths is unknown, and it is uncertain if the fatty liver is a related or just an incidental finding. Thus, while fatty liver due to alcohol appears to be a relatively benign and nonprogressive condition as a rule, a number of reservations still remain concerning the universal validity of this conclusion. Treatment of alcoholic fatty liver consists of abstention from alcohol and provision of a balanced nutritionally adequate diet. Multivitamins (initially administered parenterally to avoid malabsorption) should be given to correct vitamin deficiencies which often accompany alcoholism and are difficult to rule out in the individual patient by the routine laboratory studies. Provided dietary intake is adequate, there is no firm evidence that any special diet or food supplement is of therapeutic value. Bed rest likewise has not been proven to be of benefit. The data are controversial concerning the value of androgenic steroids in increasing hepatic lipid removal. Since some of these agents may have detrimental effects on the liver, and haste in mobilizing liver fat seems unnecessary, their use would appear to be superfluous. In most instances, with proper diet and abstention from alcohol, significant quantities of excess hepatic fat can be removed within 6 weeks (16). Digestive Diseases, VoI. 20, No. 12 (December 1975)

Kwashiorkor

In underdeveloped parts of the world kwashiorkor is a common nutritional problem (33). It is characterized by edema, pellagra-like skin changes, hair depigmentation, and impaired growth. The child, usually 1-3 years old, appears apathetic and irritable. His ability to cope with infection is impaired and such illnesses as upper respiratory and diarrheal infections, tuberculosis, and common childhood disorders tend to be more severe and last longer. Hypoproteinemia is invariably present in florid cases (33, 34). Anemia is common along with vitamin deficiency (35); hypoprothrombinemia and thrombocytopenia may lead to hemorrhagic tendency. Atrophy of various organs is observed. The small intestine is paper thin with subtotal villous atrophy (36) so that diarrhea and malabsorption are frequent. In some cases bacterial deconjugation of bile salts has been observed (37), thus contributing to the malabsorption. Fatty liver is one of the most striking characteristics of kwashiorkor (33). Jaundice is uncommon. On palpation the liver is often, but not always, enlarged; liver function tests are only mildly abnormal (38). S G O T values are less than 100 units in 75% of cases, but exceptionally high values (500-1000) may be seen (39), possibly from release of enzymes when hepatocytes distended by lipid rupture. The bromsulphalein test appears to be the most sensitive test of hepatic dysfunction, and according to Kinnear and Pretorius an abnormal value 6 days after treatment signifies a poor prognosis (38). There is evidence also that hepatic metabolism of drugs (ie, chloroquine) (40), may be impaired; however, no detailed pharmacokinetic studies have apparently been carried out. On gross inspection the liver is of bright yellow or tawny orange color and when cut much fat can be detected on the knife (33). Histologically, the severity of fatty degeneration is variable. The fat appears first as tiny droplets in the periportal cells of the hepatic lobules. As more fat accumulates the droplets coalesce 1147

HOYUMPA ET AL

pushing the nucleus to one side of the cell, while fat begins to appear in the cells closer to the central vein. Eventually most of the parenchymal cells in the lobule are filled with fat. Very severe fatty change (fat in excess of 40% of liver wet weight) is associated with a high mortality rate (41). Fat disappears in the reverse order of its appearance, leaving the centrolobular region first and the periportal area last. In most instances, the fatty change is completely reversible, although the disappearance of fat may be slow and may take several weeks. Cellular infiltration of the portal tracts may accompany the fatty change and in some cases a slight stellate portal fibrosis is observed. The rare cases seen in adults tend to be associated with more fibrosis. However, most authorities feel that frank cirrhosis does not ensue (42-44), while others hold a contrary view (45, 46). Electron microscopy (47, 48) reveals vacuolation of the cytoplasm and thickening of cell membranes as a result of the formation of numerous microvilli between adjacent liver cells. The mitochondria may be enlarged, sparsely distributed, and often in close relation to fat droplets, consistent with the view that the mitochondria play a role in the oxidation of fat. The rough endoplasmic reticulum is markedly reduced; glycogen content appears less abundant and unevenly distributed. In some instances cytoplasmic structures resembling alcoholic hyaline have been observed (39), but are nonspecific. Analysis of hepatic lipid reveals accumulation of excessive amounts of triglycerides and to some extent phospholipids, while cholesterol is normal (49-52). T h e origin of liver fat in kwashiorkor is controversial (or uncertain). Contrary to previous findings(50,51) Lewis et al (49) believes that liver fat is derived from depot fat rather than glucose. There is increased mobilization of free fatty acids (41, 49, 50, 53) from peripheral fat depots, and hepatic lipid synthesis, as measured by acetate incorporation, may proceed at an increased rate (54). The composition of liver triglyceride reflects, therefore, that seen in depot fat (49). Serum tri1148

glyceride, phospholipid, cholesterol, and pre-fllipoprotein, are decreased, but rapidly return to n o r m a l with t r e a t m e n t . T h e studies in man (55), as well as in protein-deficient primates (56), suggest that a principal cause of fatty liver in kwashiorkor is defective hepatic removal of triglyceride as the very-low-density lipoprotein (VLDL), presumably due to decreased synthesis of the V L D L apoprotein(s) (see Figure 1). In contrast, in marasmus in which the serum lipids are higher than in kwashiorkor, fatty liver is rare or absent (44, 57). Evidently, in marasmus the liver is capable of disposing excessive input of fatty acids (49); the mechanism, however, remains uncertain. The prognosis in untreated cases of kwashiorkor is poor with mortality as high as 40%. Most deaths are due to acute electrolyte disturbance or to irreversible biochemical changes in the first 24 hours and to sepsis during the next 10 days (58). Management is principally directed towards maintaining fluid and electrolyte balance, treatment of infection, and the provision of high-quality protein as well as adequate calories.

Obesity and Intestinal Bypass An interesting component of severe obesity is the p r e s e n c e of fatty liver in 6 1 - 9 4 % of cases (59-61). T h e degree of hepatic fat accumulation appears to be directly proportional to excess body weight, and the fatty liver seems to be more severe in males (62). T h e liver function tests (bilirubin, alkaline phosphatase, prothrombin time, and albumin) are abnormal in only less than 5% of cases. Abnormal BSP retention, however, is noted in about half to three fourths of cases (62, 63). This is, at least in part, due to decreased plasma volume (as percent body weight) in obese patients, resulting in a high initial plasma BSP concentration and a falsely high calculation of BSP retention at 45 min. T h e hepatic lobule is diffusely involved or the fat is randomly distributed in 76% of obese individuals, while in the remainder the fat is Digestive Diseases, Vol. 20, No. 12 (December 1975)

FATTY LIVER Table 2. JejunoUeal Bypass: Postoperative Metabolic Changes* 1, Fat Absorption A. Marked steatorrhea B. Reduction of serum lipids 2. Carbohydrate absorption A. Flat glucose tolerance curve B. Reduced D-xylose absorption C. Flat lactose tolerance curve 3. Vitamin absorption A. Decreased serum carotene, vitamins A and E B. Decreased B12 absorption 4. Fecal bile salt excretion A. Increased 5. Serum proteins A. Hypoalbuminemia B. Most essential and nonessential amino acids are decreased 6. Serum electrolytes A. Decreased K +, Ca ++, Mg ++ *The shorter the functional intestinal segment, the more profound the changes.

centrilobular, particularly in milder cases (61, 63). This latter location is in contrast to the initial periportal fat accumulation in kwashiorkor. In obesity the hepatic cell nucleus is often pushed to the periphery. On electron microscopy, the organelles appear morphologically normal and abundant glycogen stores are noted (61). In about half the cases mild lymphocytic infiltration may be seen in the portal tracts which in some cases may show slight fibrosis. More severe fibrosis and frank cirrhosis may occur, but are rare, being seen in only 4% of cases (61). Lipid analysis of hepatic tissue in obese patients reveals that the fatty change is due to a major increase in triglycerides, while free cholesterol, cholesterol esters, and phospholipid remain normal (64). The pathogenesis of fatty liver in massive obesity is obscure. However, the observations that further weight gain is accompanied by worsening of hepatic steatosis while weight loss induced by a low-calorie diet is.associated with decreased steatosis suggest that in the obese patients the fatty liver may be simply a reflection of increased total stored fat (62, 65) Digestive Diseases, VoL 20, No. 12 (December 1975)

derived from dietary sources (Figure 1). Follow-up observations of up to 33 years reveal no significant progression from fatty liver to cirrhosis in nonalcoholic (66, 67) and nondiabetic patient~ (67). Because the medical management of marked obesity often fails, however, jejunoileal bypass has been introduced by some to provide a more reliable method of weight reduction. The operation involves short-circuiting the small bowel so that only a short segment of jejunum and ileum remains functional (59, 61). With a drastically reduced absorptive area, malabsorption and consequently weight loss follow. Maximum weight loss is attained usually within 3-6 months postoperatively, after which the weight tends to stabilize as compensatory small intestinal changes develop. Both jejunum and ileum increase in diameter and thickness; the villi become broad and often folded double (68, 69). Adaptive enhancement of intestinal absorption has been noted for amino acids (70) and presumably for glucose (71), D-xylose (72),' and fat (73). In the early postoperative period, however, since absorption is drastically altered, a number of significant metabolic changes accompany weight loss (Table 2). Moreover, overt evidence of liver dysfunction may occur within 3-6 months postoperatively and is related to worsening of the pre-existing fatty liver. According to Brown et al (74), crampy abdominal pain with nausea and vomiting is an early sign of liver abnormality. The development of hepatic dysfunction tends to follow a certain sequence of events. A decrease in the uptake of technitium sulfur colloid by the Kupffer cells is the earliest detectable functional impairment. Retention of BSP develops next, followed by hypoalbuminemia and hypokalemia. Mild elevation of t r a n s a m i n a s e s and alkaline phosphatase may occur at this time. There may be fluid retention manifested by weight gain, edema, and ascites. Next, hyperbilirubinemia may ensue which may be associated with mild hypoprothrombinemia. Histologically, fatty 1149

HOYUMPA ET AL

metamorphosis is increased. Inflammatory changes similar to those seen in alcoholic hepatitis including Mallory bodies may be seen (75a). Morphologic changes and hepatic dysfunction may resolve gradually as adaptive changes develop and the weight stabilizes. However , liver failure and death may sometimes ensue (74, 75a). Severe fibrosis and cirrhosis have been documented (75b, 76). Postoperative lipid analysis of hepatic tissue reveals approximately a twofold increase in total lipids over the intraoperative value and is chiefly due to the accumulation of triglycerides (18). As in obese patients not subjected to jejunoileal bypass, the phospholipid, free cholesterol, and cholesterol esters are not significantly increased. The mechanism of increased fatty change and liver injury that follow intestinal bypass surgery has not been fully elucidated. Protein malnutrition, bile acid toxicity, and possibly bacterial toxins, singly or together, have been implicated. In studies carried out in patients 4 months postoperatively, Moxley et al (70) observed marked steatosis concomitant with a significan t decline in plasma essential and nonessential amino acids. The amino acid profile was similar to that seen in protein-calorie malnutrition. When the weight stabilized and the fatty change decreased 1-3 years postoperatively, the values returned towards normal due to improved intestinal absorption of amino acids. Thus, there is reason to suspect that protein malnutrition, just as in kwashiorkor, may play a role in postbypass fatty liver. In the latter disorder, however, the distribution of fat tends to be centrilobular initially, rather than periportal as in kwashiorkor. This difference has not been explained. In addition, the biochemical mechanism of increased fatty infiltration in postbypass surgery remains to be defined. Furthermore, protein deficiency alone is unlikely to account fully for the inflammatory changes, portal fibrosis, and cirrhosis which may follow, so that other factors also have to be considered. Inasmuch as experimental liver injury may be produced 1150

by bile salts, especially lithocholic acid, bile salt hepatoxicity has been postulated as one etiologic factor (76). Indeed, jejunoileal bypass has been shown to result in abnormal bile acid metabolism (78-80). A marked increase of serum lithocholic acid, as well as accumulation of chenodeoxycholic acid, in both serum and liver have been reported (80). Based on these observations it was suggested that bile acids, in association with protein deficiency, may be important in the pathogenesis of post-jejunoilealbypass (81), However, the possibility that the elevation of serum bile acids may be secondary to the liver disease (caused by some other unknown factor) should not be ignored. Alternately, or in addition, it is possible that a toxin is released from the defunctionalized loop. In support of this hypothesis is the observation that the administration of Vibramycin in dogs with jejunoileal bypass reduced the overgrowth of Bacteroides species in the excluded loop and prevented progressive hepatic deterioration (82). Although the toxin(s) has not been identified and the mechanism is obscure, the practical implication of these recent observations is obvious and requires clinical confirmation. In patients in whom progressive liver failure develops following jejunoileal bypass, dismantling of the intestinal short-circuiting is often necessary to reverse the disease process. The timing of surgery is critical, and the severely ill patient may require a period of parenteral alimentation prior to operative intervention. Diabetes

Fatty liver is commonly associated with diabetes mellitus. Three circumstances exist in which liver disease and diabetes are related. The two conditions may occur coincidentally, diabetes may follow liver disease, or liver disease may be secondary to diabetes. A comprehensive discussion of the relationship between liver disease in general and diabetes mellitus is given elsewhere (83). The present discussion deals only with fatty liver resulting from diabetes. Digestive Diseases, Vol. 20, No. 12 (December 1975)

FATTY LIVER

Fatty liver resulting from diabetes is determined by the type of diabetes (maturity-onset obese or insulin-dependent juvenile) and whether or not the insulin-requiring diabetic is well controlled. There is great variability in the incidence of fatty liver in diabetes and ranges from 21-78% (average 50~ of cases (83). Fatty liver occurs more frequently in patients dying of severe ketoacidosis (51%) than in those who had no ketoacidosis (12.7%) (84). The severity of hepatic steatosis in maturity-onset obese diabetes is in direct proportion to the degree of obesity and to advancing age, but not to the duration of diabetes or to the adequacy of diabetic control. Nevertheless, fatty liver occurs more frequently in patients who are not on insulin (63% of cases) than in those who are on insulin (17070) (85). In patients with diabetes mellitus, the liver function tests may be abnormal (86, 87). Leevy et al (86) noted abnormal liver function tests in 38.9% of 380 diabetic patients. In this study 30 selected diabetic patients underwent a liver biopsy, and the results were correlated with the liver function tests. Of 8 patients with normal liver function tests, 3 had fatty liver on liver biopsy. Of the remaining 22 with abnormal liver function tests, the biopsy was normal in 9, showed fatty liver in 5, and cirrhosis in 8. In 15 patients with abnormal liver function tests, it was determined by history that diabetes requiring insulin preceded liver dysfunction. In these cases the liver disease was deemed secondary to diabetes and at liver biopsy, 5 had normal histology, 6 had fatty liver, and 4 had cirrhosis. In diabetic patients with fatty liver, the serum bilirubin, flocculation studies, and albumin are usually normal or only mildly deranged. In contrast, increased BSP retention is more common

(37.5%). Histologic examination reveals that in 43.5% cases (88) the distribution of fat in diabetic hepatic steatosis is centrilobular, but is periportal in 26.1%, or diffuse in 30.4%. The fat globules usually displace the hepatocyte nucleus to the periphery. Recent studies in sheep (89) and Digestive Diseases, VoL 20, No. 12 (December 1975)

rats (90-92) with experimental diabetes reveal marked enlargement and distortion of the mitochondria which in ketotic rats correlate with decreased oxidative phosphorylation and enhanced oxidation of palmitate to acetoacetate (90). There is also reduction of protein synthesis by polysome preparations in vitro (91) and detachment of ribosomes from the endoplasmic reticulum (92). Insulin treatment promptly reverses both the mitochondrial and ribosomal alterations. These studies of organelle morphologic abnormality which correlate with in vitro biochemical alteration may be clues to the pathogenesis of liver abnormalities in human insulin-dependent diabetes. In addition to these light- and electron-microscopic changes, nuclear glycogen seen in 60-75% of patients is often a prominent finding in diabetes mellitus (83). Hepatocytes with nuclear glycogen are frequently periportal in location, and the amount of glycogen in the nucleus varies inversely with that in the cytoplasm. Although nuclear glycogen is nonspecific, there are those who attach significance to the association of fatty change and abundant nuclear glycogen in the diagnosis of diabetes mellitus (93). The mechanism of fatty liver varies with the different types of diabetes. In juvenile diabetes insulin deficiency is the rule. Insulin deficiency may be accompanied by increased lipolysis (94), decreased lipoprotein synthesis (95), and reduced removal of lipid from plasma (96). These conditions predispose juvenile diabetics to hyperlipemia and hepatic steatosis (Figure 1), which are reversed by insulin therapy. On the other hand, in maturity-onset diabetes plasma insulin levels are elevated (97, 98) with an increase of plasma FFA. The degree of hepatic fatty change is proportional to the obesity, and steatosis may be related to increased ingestion of fat or carbohydrate (Figure 1). Calorie restriction is followed by weight loss and decrease in hepatic fat: In general the presence of fatty liver does not greatly affect prognosis in diabetes mellitus. Whether or not hepatic steatosis in diabetes 1151

HOYUMPA ET AL

gives rise to cirrhosis has been debated for some time. Some investigators (83, 88, 99) report an increased incidence (7-32%) of cirrhosis in diabetic patients, while others deny such a relationship (84). The uncertainty generated by this discrepancy results partly from (1) the lack or inability in many reports to determine if diabetes preceded, followed, or coincidentally accompanied the liver disease and (2) insufficient data regarding alcohol consumption, anicteric hepatitis, or other factors which by themselves may produce cirrhosis. Treatment is directed chiefly towards the underlying disorder: insulin for insulin-dependent juvenile diabetics and weight reduction with carbohydrate-poor and protein-rich diet in adult-onset diabetics. I d i o p a t h i c Fatty Liver of P r e g n a n c y A c u t e f a t t y l i v e r o f p r e g n a n c y is a r a r e dis-

order of unknown cause occurring primarily in the third trimester. Sheehan's description of the disorder is classic (100). The pertinent clinical and laboratory features as observed in histologically proven cases reported in the literature (101-131) and two other cases we have obTable 3. Idiopathic Acute Fatty Liver of Pregnancy: Key Features of 50 Cases 1. Age (years) 2. R a c e ( N = 33) 3. Parity(N = 31)

Mean 28 (Range 16-42) Caucasian 26; Negro 4; Mexican 2; Chinese 1 0 = 10 cases 1=6 2=4 3=3 >3 = 8

4. Weeks of gestation (N = 41)

5. Pancreatitis (N = 50) 6. Fatty change in kidneys (N - 50) 7. Mortality (N ~ 49) Maternal Fetal

1152

>36 wks = 27 30-35 wks = 12 28-29 wks = 2 20% 24% 80% 74%

Table 4. Idiopathic Fatty Liver of Pregnancy: Clinical Features of 50 Cases Jaundice Coma

Nausea and vomiting* Hematemesis Fever

Abdominal pain Headache Palpable liver Spider nevi Convulsions Petechiae Pruritus

95% 84% 78% 53% 34% 26% 26% 14% 8% 7% 5% 3%

*Often first complaint.

served are given in Tables 3-5. Patients who received tetracycline were excluded. At 36-40 weeks of gestation, there is a sudden onset of severe vomiting and epigastric pain followed by jaundice in a few days. These symptoms progress rapidly. The jaundice becomes more intense, and the vomitus becomes bloody. Headache is sometimes present. The patient usually delivers a stillborn baby, becomes comatose and, according to Sheehan, usually dies within 3 days of delivery. Rarely, symptoms may start by 28 weeks of gestation (108, 110) or may not appear until after delivery (104, 108, 119). Jaundice is variable in intensity, the bilirubin ranging from 3 to 36.4 mg/100 ml, average 13.4 mg/100 ml. An occasional patient may remain anicteric throughout the illness (112). Severe thirst may precede the persistent vomiting for 1-2 days. Hematemesis most frequently results from multiple acute mucosal ulcerations, involving the esophagus and stomach, and occasionally from bleeding varices (121) or a Mallory-Weiss tear (119). The bleeding tendency is aggravated by hypoprothrombinemia and other coagulation defects (119), including disseminated intravascular coagulation (130, 131). Other less constant features include preeclampsia, convulsions, itching, and petechiae. Tachycardia and hypotension are common and are probably related to blood loss. The liver is usually not palpable. Ascites and edema are Digestive Diseases, Voh 20, No. 12 (December 1975)

FATTY LIVER Table 5. Idiopathic Acute Fatty Liver of Pregnancy: Laboratory Findings

WBC (mm 3) BUN (mg/100 ml) Total bilirubin (mg/100 ml) SGOT (units) SGPT (units) Alkaline phosphatase Prothrombin time

11,200-54,000 (>20,000 in 60%) 16-450 (>20in93%) 3-36.4 (average, 13.4) (~

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Digestive Diseases, Vol. 20, No. 12 (December 1975)

significant changes. These studies suggest that a syndrome similar, but not necessarily identical, to the disorder described by Reye et al (143) may result from chemical toxins and viral agents acting in concert. A condition known as fatty-liver-and-kidney syndrome (FLKS) in chickens is said to resemble Reye's syndrome in children and has been suggested as an experimental model of this disease (170b). The prognosis of Reye's syndrome has improved since the initial reports but remains poor. In the first 200 reported cases, mortality was 80% (171,172). Recent papers indicate a lower mortality of 25-70% (144, 15i, 156), perhaps because milder cases are diagnosed, treatment is begun earlier~ or management is better. Between 10% and 30% of the survivors show evidence of CNS sequelae such as mental impairment, seizures, blindness, or hemiplegia (145, 173). Again, it is not clear whether this Variance in rate of sequelae is due to improved cai"e or to differences in severity of the disease. The assessment of the relative eff• of different therapies is difficult, as it is not yet clear which of the measurable abnormalities are the best indices of prognosis. Recent studies suggest that creatine phosphokinase and lactic dehydrogenase isoenzyme activities and serum amino acid patterns might prove valuable in determining prognosis and evaluating the efficacy of specific therapeutic measures (147,173). Therapy for Reye's syndrome is empirical, and no therapy has been evaluated in a controlled manner. General supportive measures are aimed at (1) correction of acidosis, (2) infusions of glucose to maintain normal blood glucose levels, (3) reduction of intracranial pressure with fluid restriction and mannitol, (4) reduction in the influx of nitrogenous product from the gut with oral neomycin, and (5) assisted respiration if necessary. These measures comprise a rational approach to treatment and should be started as soon as the diagnosis is suspected. However, even these supportive measures have not been critically assessed as to individual benefit. 1159

HOYUMPA ET AL

Specific therapy has been directed toward removal of ammonia or other postulated toxins from the circulation (144, 174). Dialysis or exchange transfusion have been used by a number of investigators and are useful in correcting refractory metabolic abnormalities. Dramatic results were reported with peritoneal dialysis, where 9 of 11 patients treated in this manner survived (175). However, enthusiasm for this treatment has lessened since 9 of the next 11 patients died (176). In addition to the potential benefits of dialysis, exchange transfusion also corrects bleeding disorders due to clotting-factor deficiencies, may rid the blood of undialyzable agents, and theoretically may provide substrate for liver or brain. Since the hepatic lesion in Reye's syndrome is reversible, exchange transfusion may prove more effective in Reye's syndrome than with encephalopathies associated with extensive or irreversible hepatic parenchymal damage. It should be emphasized, however, that so far no controlled studies of the efficacy of this procedure have been carried out. In summary, Reye's syndrome may represent the effects of several different etiologic agents acting on the same metabolic pathway(s). Prodromal viral infection(s), possibly inherent metabolic derangements, and exogenous toxin(s) may act synergistically to cause ultrastructural changes and metabolic aberrations to some extent in all tissues. Hepatic fat accumulation in Reye's syndrome probably results from both an increase in uptake from lipolysis of peripheral fat and to some extent an increase in synthesis from lipogenic amino acids, lactate, and pyruvate. A major defect might also be due to a decrease in s~,nthesis of apoprotein as reflected by the absence of V L D L particles in the Golgi (Figure 1). Other hepatic metabolic derangements may result from altered mitochondrial function resulting in decreased bioenergetic potential (ATP, creatine phosphate) of the cells. The effect of this, seen particularly in liver and brain, would be to induce an accumulation of various endotoxins which result in further aberration of CNS function.

Early diagnosis and detailed documentation of biochemical abnormalities in plasma and accessible tissues are imperative to document the pathogenesis of Reye's syndrome. The development of an experimental animal model, which correlates CNS findings with those in other tissues, may ultimately provide the most useful information. For the moment, detailed epidemiological studies and evaluation of structural and biochemical changes in liver, muscle, leukocytes, and when possible, brain tissue, are the most hopeful lines of study. A careful assessment of mitochondrial metabolism in liver and muscle of patients with Reye's syndrome is overdue. Since some toxic agent appears likely in the pathogenesis and since hepatic necrosis is not a feature (therefore hepatic regeneration is not essential for recovery as in fulminant hepatitis), the most promising method of removal is through exchange transfusion. But because this procedure is unproven and carries some risk, it should only be performed as part of a controlled trial. This type of systematic approach should ultimately define pathogenesis and rationalize therapy.

1160

Digestive Diseases, Vol. 20, No. 12 (December 1975)

Fatty Liver in I n h e r i t e d M e t a b o l i c Disorders

A number of inherited disorders of lipid metabolism may be associated with fatty liver. Space does not allow a detailed discussion of each condition. These conditions include abetalipoproteinemia, Tangier disease, Wolman's disease, and cholesterol ester storage disease. A comparison of their salient features is given in Table 7. The morphologic characteristics of the liver in Nieman-Picks, Gaucher's disease, and Hunter-Hurler's syndrome are given elsewhere by Volk and Wallace (188). Fatty liver may also accompany inherited disorders of carbohydrate metabolism [galactosemia (189-193), hereditary fructose intolerance due to fructose-lphosphate aldolase (193) or fructose diphosphatase (195) deficiency, glycogen type I storage disease (196)] as well as abnormal copper

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metabolism (Wilson's disease) (197) and phytanic acid storage (Refsum's syndrome)(198, 199). In addition, there are reports of familial hepatic steatosis which remain to be better defined (200).

CONCLUDING

REMARKS

It is evident from the foregoing discussion that steatosis is a common and nonspecific response of the liver to different forms of acquired injury or inherited metabolic derangement. T h e clinical impact of fatty liver is variable. It can be acute and fulminating, as in fatty liver of pregnancy and Reye's syndrome, or insidious and benign, as in the fatty liver of obesity and diabetes. Inasmuch as its presence is best detected by histological examination, the differential diagnosis may be aided to some extent by noting the distribution of fat in the hepatic lobule and the location of the nucleus in the hepatocyte (Table 8). Thus, it can be seen that in the more common types of fatty liver (alcoholic, kwashiorkor, obesity, post-jejunoileal-bypass and diabetes) the cytoplasm of the hepatocyte is distended by large fat globules which displace the nucleus peripherally. On the other hand, fine intracellular fat vacuoles which do not displace the nucleus should arouse suspicion of idiopathic fatty liver of pregnancy, tetracycline toxicity, Reye's syndrome, or cholesterol ester storage disease. Moreover, a centrolobular fat distribution should suggest idiopathic fatty liver of pregnancy rather than tetracycline toxicity or Reye's syndrome. In very severe cases, however, differentiation based on lobular fat distribution can be obscured. For instance, in milder cases the usual periportal fatty change in kwashiorkor and the centrolobular fat distribution in obesity both become diffuse in the severe forms of these disorders. T h e reason for the tendency of accumulated fat to form large globules and displace the nucleus in some cases and not in others or to be initially distributed centrally in some but periportally in others remains obscure. It is also apparent that knowledge of the 1162

biochemical lesion(s) involved is fragmentary or nonexistent. This is partly due to the present incomplete knowledge of the physiology of fat metabolism. Therefore, there is a need to further investigate the different steps in the transport, uptake, formation ("packaging"), and secretion of lipids by the liver and relate these to the different structures and functions of the hepatocyte organelles, both under normal and abnormal conditions. Such an integrated approach, requiring the contributions of various disciplines, should provide a firm basis for the identification of the specific processes impaired, should result in the improved understanding of the pathogenesis and should rebound, hopefully, to a more rational therapeutic approach to hepatic steatosis. ACKNOWLEDGMENTS

The authors are grateful to Mrs. Betty McCuiston for typing the manuscript and to Dr. Suhayl Uthman for helping compile the data in Tables 3-6. REFERENCES

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FATTY LIVER

8. Stein O, Bar-on H, Stein Y: Lipoprotein and the liver. Progress in Liver Disease, Vol IV. H Popper and F Schaffner (eds). New York and London, Grune and Stratton, 1972, pp 45-65 9. Robinson DS, French JE: Heparin, the clearing factor lipase, and fat transport. Pharmacol Rev 12:241-263, 1960 10. Raben MS: Regulation of fatty acid release with particular reference to pituitary factors. Adipose Tissue, Handbook of Physiology, Vol 5, (Am Physiol Soc, Washington, D.C.). Baltimore, Williams and Wilkins, 1965, pp 331334 11. Carlson LA, Balty PR: Inhibition of lipid mobilization. Adipose Tissue, Handbook of Physiology, Vol 5 (Am Physiol Soc, Washington, D.C.). Baltimore, Williams and Wilkins, 1965, pp 557-574 12. Ockner RK, Manning JA, Poppenhauser RB, Ho WKL: A binding protein for fatty acids in cytosol of intestinal mucosa, liver, myocardium and other tissues. Science 177:56-58, 1972 13. Farber E: On the pathogenesis of fatty liver. Gastroenterology 50:137-141, 1966 14. Roheim PS, Miller L, Eder HA: The formation of plasma lipoproteins from apoprotein in plasma. J Biol Chem 240:2994-3001, 1965 15. Hamilton RL, Kaydes H J: The liver and the formation of normal and abnormal plasma lipoprotein. Biochemistry of Disease, Vol 5, The Liver: Normal and Abnormal Function, Part A. FF Becker (ed). New York, Marcel Dekker, 1974, pp 531-588 16. Leevy CM, Zinke MR, White T J, Guessi AM: Clinical observations on the fatty liver. Arch Intern Med 92:527-541, 1953 17. Leery CM: Fatty liver: A study of 270 patients with biopsy-proven fatty liver and a review of the literature. Medicine 41:249, 1962 18. Holzbach RT, Wieland RG, Leiber CS, DeCarli LM, Koepke KR, Green SG: Hepatic lipid in morbid obesity. Assessment at end subsequent to jejunoileal bypass. N Engl J Med 290:296-299, 1974 19. Rubin E, Lieber CS: Alcohol-induced hepatic injury in non-alcoholic volunteers. N Engl J Med 278:869-876, 1968 20. Lieber CS: Effects of ethanol upon lipid metabolism. Lipids 9:103-t 16, 1974 21. Lieber CS, Spritz N, DeCarli LM: Role of Digestive Diseases, Vol. 20, No. 12 (December 1975)

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