http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(2): 128–130 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2013.879642
LETTER TO THE EDITOR
AApoAIL75P amyloidosis causes cirrhosis-like appearance of the liver in the absence of laboratory or clinical signs of hepatic dysfunction Yesim Avsar1, Tilmann Spieker2, Iyad Kabar1, Christoph Roecken3, Heiner Wolters4, and Hartmut Schmidt1 1
Department of Transplant Medicine, University Hospital Muenster, Muenster, Germany, 2Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, Muenster, Germany, 3Institute of Pathology, Christian Albrecht University, Kiel, Germany, and 4Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
Hereditary systemic amyloidosis is a genetically and clinically heterogeneous group of diseases caused by deposits of insoluble proteins within tissues. The majority of cases are due to a mutation of the transthyretin gene (TTR); however, variants of other proteins such as apolipoproteinAI (ApoAI) [1] have been found to be associated with hereditary amyloidosis. AApoAI amyloidosis has been first described by van Allen et al. [2] in 1969 in a family from Iowa (AApoAIIowa) with the main clinical features being peripheral neuropathy, nephropathy, and peptic ulcer disease. Since then several more cases of AApoAI amyloidosis with varying mutations have been reported. Interestingly the phenotypic expression is highly variable. Amyloid deposits may affect mainly kidneys in some patients [3,4], while others may display primarily cardiac [5,6], neuronal [7], or gastrointestinal symptoms [3]. Even kindreds with the same protein variant present with differing degrees of expression. Patients may display isolated laboratory abnormalities while others experience clinically relevant organ dysfunction confined to one or more organ systems [8–11]. One of the mutations found to be associated with AApoAI amyloidosis is AApoAIL75P, characterized by a thymine to cytosine transition at position 1772 of the ApoAI gene, resulting in a proline for leucine substitution at codon 75 of the polypeptide chain. AApoAIL75P amyloidosis has been first described by Obici et al. [5] in an Italian family and later in a further 13 unrelated patients [11]. Affected individuals were found to have systemic amyloidosis with predominant involvement of liver and kidneys. Interestingly, only few patients had a corresponding family history, while most individuals appeared to have sporadic disease. Testicular involvement as an early manifestation of AApoAIL75P amyloidosis has been reported by Scalvini et al. [12]. We report a patient with AApoAI amyloidosis with an interesting macroscopic liver presentation not matching clinical or laboratory findings. Our patient is a 68-year old Address for correspondence: Yesim Avsar, MD, Department of Transplant Medicine, University Hospital Muenster, Albert-SchweitzerCampus 1, Building A14, 48149 Muenster, Germany. Tel: +49 251 83 57935. Fax: +49 251 83 57949. E-mail: [email protected]
Keywords Apolipoprotein AI, familial amyloidotic polyneuropathy, hepatic amyloidosis, hereditary amyloidosis, liver transplantation History Received 17 July 2013 Revised 18 December 2013 Accepted 22 December 2013 Published online 25 March 2014
woman, diagnosed with chronic kidney disease with glomerular proteinuria at the age of 50 years. Diagnosis of AApoAIL75P amyloidosis, formerly known as p.Leu75Pro ApoAI amyloidosis [13], was made 7 years later with a kidney biopsy and genetic analysis of blood samples. The family history was significant for ‘‘heart disease’’ in the patient’s father, but an amyloidosis specific history could not be elicited. The patient’s disease progressed in the form of polyneuropathy primarily affecting lower extremities. Further progression involved the heart, causing mild concentric left ventricular hypertrophy and sick-sinus-syndrome requiring implantation of a pacemaker. Renal function worsened to stage IV chronic kidney disease. Ultrasonography and CT-imaging of the liver revealed a nodular surface and irregular parenchyma. The patient refused a liver biopsy, preventing further diagnostics such as histopathological analysis. However, liver function tests including aspartate and alanine transaminases, gamma glutamyl transpeptidase, alkaline phosphatase, albumin, bilirubin, and coagulation parameters remained within normal limits throughout the clinical course. Clinical signs and symptoms indicating the presence of hepatic dysfunction were absent. At age 68 years, the patient underwent combined liver–kidney transplantation to restore renal function and to prevent the progression of polyneuropathy. Upon exploration of the host liver, a cirrhosis-like appearance was macroscopically evident (Figure 1A). With 2130 g, the liver was markedly enlarged, with a nodular surface and firm parenchyma,
DOI: 10.3109/13506129.2013.879642
Unique form of liver involvement with AApoAI amyloidosis
129
Figure 1. (A) Cirrhosis-like nodular appearance of AApoAI explant liver. Congo red staining of AApoAI explant liver. (B) Congo red stained section viewed under polarizing microscopy. Amyloid deposits exhibit apple-green birefringence (scale bar ¼ 100 mm). (C) Same Congo red stained section viewed under fluorescent microscopy. Amyloid deposits appear yellow-orange (scale bar ¼ 100 mm). Histopathological findings in AApoAI explant liver. (D) Hepatic steatosis (hematoxylin and eosin staining; scale bar ¼ 75 mm). (E) Hepatic AApoAI amyloidosis. Large confluent amyloid deposits were found in the liver parenchyma (hematoxylin and eosin staining; scale bar ¼ 300 mm). (F) Anti-ApoAI-immunostaining. Amyloid deposits stained with antibodies directed against ApoAI. (hematoxylin and eosin staining, scale bar ¼ 75 mm). (G) Anti--ligth chain immunostaining. No immunostaining was found with an antibody directed against -light chain (scale bar ¼ 75 mm).
without focal lesions. Histopathologically, liver architecture was preserved with areas of moderate to severe steatosis (Figure 1D). Large confluent deposits of amyloid were found with a rather unique jigsaw-like distribution pattern (Figure 1E), mainly in the parenchyma in zones 2 and 3, often enclosing a central hepatic vein. This distribution pattern was rather different from the typical extensive perisinusoidal deposition pattern of AL amyloidosis with liver cell atrophy. Viewed under polarized light, the amyloid deposits displayed the typical apple green birefringence after Congo red staining (Figure 1B and C), and there was strong and homogenous immunoreaction for AApoAI (Figure 1F). No immunostaining was seen with antibodies directed against - and k-light chains (Figure 1G), AA amyloid, fibrinogen, lysozyme, and transthyretin. The portal tracts were morphologically unremarkable, with some lymphocytic infiltrates. There was only minimal evidence of iron deposits in stellate cells.
No abnormal glycogen storage was observed. Electron microscopy detected extracellular fibrils typical for amyloid as well as cytoplasmic accumulation of lysosomes and concentric lamellar inclusion bodies. The phenotypic picture of AApoAI amyloidois evidently differs among affected patients. Even among related subjects with the same mutation, the degree of phenotypic expression varies significantly [7,8]. While some reports describe affected subjects with a completely unremarkable liver, others reported of histopathologically evident hepatic amyloidosis in patients without any clinical or laboratory correlate [8,14]. Booth et al. [8] described a Spanish family with a deletion mutation of the ApoAI gene, presenting mainly with hepatic dysfunction, eventually leading to death from liver failure. Shaz et al. reported of two patients with AApoAI amyloidosis, whose livers where intended to be used as domino organs. Liver function tests and gross liver
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appearance were unremarkable. However, histopathological analysis of the explant livers revealed extensive amounts of amyloid deposits, rendering the livers unsuitable for transplantation [14]. The exact mechanism that causes mutant ApoAI variants to form amyloid is still to be elucidated. The differing predilection of the amyloid to one organ system over another in different patients remains, therefore, unclear and makes it difficult to predict the extension of hepatic involvement in affected persons. Our case of a patient with a macroscopically evident amyloidotic liver in the absence of clinical and laboratory correlates highlights the unpredictable clinical course of AApoAI amyloidosis.
Amyloid, 2014; 21(2): 128–130
6.
7.
8.
9.
Declaration of interest The authors report no conflict of interest.
10.
References 1. Nichols WC, Dwulet FE, Liepnieks J, Benson MD. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun 1988;156:762–8. 2. Van Allen MW, Frohlich JA, Davis JR. Inherited predisposition to generalized amyloidosis. Clinical and pathological study of a family with neuropathy, nephropathy, and peptic ulcer. Neurology 1969; 19:10–25. 3. Joy T, Wang J, Hahn A, Hegele RA. APOA1 related amyloidosis: a case report and literature review. Clin Biochem 2003;36:641–5. 4. Gillmore JD, Stangou AJ, Lachmann HJ, Goodman HJ, Wechalekar AD, Acheson J, Tennent GA, et al. Organ transplantation in hereditary apolipoprotein AI amyloidosis. Am J Transplant 2006;6: 2342–7. 5. Obici L, Bellotti V, Mangione P, Stoppini M, Arbustini E, Verga L, Zorzoli I, et al. The new apolipoprotein A-I variant leu(174) - -4gt; Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils
11.
12.
13.
14.
are constituted by the 93-residue N-terminal polypeptide. Am J Pathol 1999;155:695–702. Hamidi Asl K, Liepnieks JJ, Nakamura M, Parker F, Benson MD. A novel apolipoprotein A-1 variant, Arg173Pro, associated with cardiac and cutaneous amyloidosis. Biochem Biophys Res Commun 1999;257:584–8. Testro AG, Brennan SO, Macdonell RAL, Hawkins PN, Angus PW. Hereditary amyloidosis with progressive peripheral neuropathy associated with apolipoprotein AI Gly26Arg: outcome of hepatorenal transplantation. Liver Transpl 2007;13:1028–31. Booth DR, Tan SY, Booth SE, Tennent GA, Hutchinson WL, Hsuan JJ, Totty NF, et al. Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene. J Clin Invest 1996;97:2714–21. Caballerı´a J, Bruguera M, Sole´ M, Campistol JM, Rode´s J. Hepatic familial amyloidosis caused by a new mutation in the apolipoprotein AI gene: clinical and pathological features. Am J Gastroenterol 2001;96:1872–6. Coriu D, Dispenzieri A, Stevens FJ, Murphy CL, Wang S, Weiss DT, Solomon A. Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro. Amyloid 2003;10:215–23. Obici L, Palladini G, Giorgetti S, Bellotti V, Gregorini G, Arbustini E, Verga L, et al. Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families. Gastroenterology 2004;126:1416–22. Scalvini T, Martini PR, Gambera A, Tardanico R, Biasi L, Scolari F, Gregorini G, et al. Spermatogenic and steroidogenic impairment of the testicle characterizes the hereditary leucine-75proline apolipoprotein a-I amyloidosis. J Clin Endocrinol Metab 2008;93:1850–3. Sipe JD, Benson MD, Buxbaum JN, Ikeda S-I, Merlini G, Saraiva MJM, Westermark P. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 2012;19:167–70. Shaz BH, Lewis WD, Skinner M, Khettry U. Livers from patients with apolipoprotein A-I amyloidosis are not suitable as ‘‘domino’’ donors. Mod Pathol 2001;14:577–80.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTER TO THE EDITOR
AApoAIL75P amyloidosis causes cirrhosis-like appearance of the liver in the absence of laboratory or clinical signs of hepatic dysfunction Yesim Avsar1, Tilmann Spieker2, Iyad Kabar1, Christoph Roecken3, Heiner Wolters4, and Hartmut Schmidt1 1
Department of Transplant Medicine, University Hospital Muenster, Muenster, Germany, 2Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, Muenster, Germany, 3Institute of Pathology, Christian Albrecht University, Kiel, Germany, and 4Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
Hereditary systemic amyloidosis is a genetically and clinically heterogeneous group of diseases caused by deposits of insoluble proteins within tissues. The majority of cases are due to a mutation of the transthyretin gene (TTR); however, variants of other proteins such as apolipoproteinAI (ApoAI) [1] have been found to be associated with hereditary amyloidosis. AApoAI amyloidosis has been first described by van Allen et al. [2] in 1969 in a family from Iowa (AApoAIIowa) with the main clinical features being peripheral neuropathy, nephropathy, and peptic ulcer disease. Since then several more cases of AApoAI amyloidosis with varying mutations have been reported. Interestingly the phenotypic expression is highly variable. Amyloid deposits may affect mainly kidneys in some patients [3,4], while others may display primarily cardiac [5,6], neuronal [7], or gastrointestinal symptoms [3]. Even kindreds with the same protein variant present with differing degrees of expression. Patients may display isolated laboratory abnormalities while others experience clinically relevant organ dysfunction confined to one or more organ systems [8–11]. One of the mutations found to be associated with AApoAI amyloidosis is AApoAIL75P, characterized by a thymine to cytosine transition at position 1772 of the ApoAI gene, resulting in a proline for leucine substitution at codon 75 of the polypeptide chain. AApoAIL75P amyloidosis has been first described by Obici et al. [5] in an Italian family and later in a further 13 unrelated patients [11]. Affected individuals were found to have systemic amyloidosis with predominant involvement of liver and kidneys. Interestingly, only few patients had a corresponding family history, while most individuals appeared to have sporadic disease. Testicular involvement as an early manifestation of AApoAIL75P amyloidosis has been reported by Scalvini et al. [12]. We report a patient with AApoAI amyloidosis with an interesting macroscopic liver presentation not matching clinical or laboratory findings. Our patient is a 68-year old Address for correspondence: Yesim Avsar, MD, Department of Transplant Medicine, University Hospital Muenster, Albert-SchweitzerCampus 1, Building A14, 48149 Muenster, Germany. Tel: +49 251 83 57935. Fax: +49 251 83 57949. E-mail: [email protected]
Keywords Apolipoprotein AI, familial amyloidotic polyneuropathy, hepatic amyloidosis, hereditary amyloidosis, liver transplantation History Received 17 July 2013 Revised 18 December 2013 Accepted 22 December 2013 Published online 25 March 2014
woman, diagnosed with chronic kidney disease with glomerular proteinuria at the age of 50 years. Diagnosis of AApoAIL75P amyloidosis, formerly known as p.Leu75Pro ApoAI amyloidosis [13], was made 7 years later with a kidney biopsy and genetic analysis of blood samples. The family history was significant for ‘‘heart disease’’ in the patient’s father, but an amyloidosis specific history could not be elicited. The patient’s disease progressed in the form of polyneuropathy primarily affecting lower extremities. Further progression involved the heart, causing mild concentric left ventricular hypertrophy and sick-sinus-syndrome requiring implantation of a pacemaker. Renal function worsened to stage IV chronic kidney disease. Ultrasonography and CT-imaging of the liver revealed a nodular surface and irregular parenchyma. The patient refused a liver biopsy, preventing further diagnostics such as histopathological analysis. However, liver function tests including aspartate and alanine transaminases, gamma glutamyl transpeptidase, alkaline phosphatase, albumin, bilirubin, and coagulation parameters remained within normal limits throughout the clinical course. Clinical signs and symptoms indicating the presence of hepatic dysfunction were absent. At age 68 years, the patient underwent combined liver–kidney transplantation to restore renal function and to prevent the progression of polyneuropathy. Upon exploration of the host liver, a cirrhosis-like appearance was macroscopically evident (Figure 1A). With 2130 g, the liver was markedly enlarged, with a nodular surface and firm parenchyma,
DOI: 10.3109/13506129.2013.879642
Unique form of liver involvement with AApoAI amyloidosis
129
Figure 1. (A) Cirrhosis-like nodular appearance of AApoAI explant liver. Congo red staining of AApoAI explant liver. (B) Congo red stained section viewed under polarizing microscopy. Amyloid deposits exhibit apple-green birefringence (scale bar ¼ 100 mm). (C) Same Congo red stained section viewed under fluorescent microscopy. Amyloid deposits appear yellow-orange (scale bar ¼ 100 mm). Histopathological findings in AApoAI explant liver. (D) Hepatic steatosis (hematoxylin and eosin staining; scale bar ¼ 75 mm). (E) Hepatic AApoAI amyloidosis. Large confluent amyloid deposits were found in the liver parenchyma (hematoxylin and eosin staining; scale bar ¼ 300 mm). (F) Anti-ApoAI-immunostaining. Amyloid deposits stained with antibodies directed against ApoAI. (hematoxylin and eosin staining, scale bar ¼ 75 mm). (G) Anti--ligth chain immunostaining. No immunostaining was found with an antibody directed against -light chain (scale bar ¼ 75 mm).
without focal lesions. Histopathologically, liver architecture was preserved with areas of moderate to severe steatosis (Figure 1D). Large confluent deposits of amyloid were found with a rather unique jigsaw-like distribution pattern (Figure 1E), mainly in the parenchyma in zones 2 and 3, often enclosing a central hepatic vein. This distribution pattern was rather different from the typical extensive perisinusoidal deposition pattern of AL amyloidosis with liver cell atrophy. Viewed under polarized light, the amyloid deposits displayed the typical apple green birefringence after Congo red staining (Figure 1B and C), and there was strong and homogenous immunoreaction for AApoAI (Figure 1F). No immunostaining was seen with antibodies directed against - and k-light chains (Figure 1G), AA amyloid, fibrinogen, lysozyme, and transthyretin. The portal tracts were morphologically unremarkable, with some lymphocytic infiltrates. There was only minimal evidence of iron deposits in stellate cells.
No abnormal glycogen storage was observed. Electron microscopy detected extracellular fibrils typical for amyloid as well as cytoplasmic accumulation of lysosomes and concentric lamellar inclusion bodies. The phenotypic picture of AApoAI amyloidois evidently differs among affected patients. Even among related subjects with the same mutation, the degree of phenotypic expression varies significantly [7,8]. While some reports describe affected subjects with a completely unremarkable liver, others reported of histopathologically evident hepatic amyloidosis in patients without any clinical or laboratory correlate [8,14]. Booth et al. [8] described a Spanish family with a deletion mutation of the ApoAI gene, presenting mainly with hepatic dysfunction, eventually leading to death from liver failure. Shaz et al. reported of two patients with AApoAI amyloidosis, whose livers where intended to be used as domino organs. Liver function tests and gross liver
130
Y. Avsar et al.
appearance were unremarkable. However, histopathological analysis of the explant livers revealed extensive amounts of amyloid deposits, rendering the livers unsuitable for transplantation [14]. The exact mechanism that causes mutant ApoAI variants to form amyloid is still to be elucidated. The differing predilection of the amyloid to one organ system over another in different patients remains, therefore, unclear and makes it difficult to predict the extension of hepatic involvement in affected persons. Our case of a patient with a macroscopically evident amyloidotic liver in the absence of clinical and laboratory correlates highlights the unpredictable clinical course of AApoAI amyloidosis.
Amyloid, 2014; 21(2): 128–130
6.
7.
8.
9.
Declaration of interest The authors report no conflict of interest.
10.
References 1. Nichols WC, Dwulet FE, Liepnieks J, Benson MD. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun 1988;156:762–8. 2. Van Allen MW, Frohlich JA, Davis JR. Inherited predisposition to generalized amyloidosis. Clinical and pathological study of a family with neuropathy, nephropathy, and peptic ulcer. Neurology 1969; 19:10–25. 3. Joy T, Wang J, Hahn A, Hegele RA. APOA1 related amyloidosis: a case report and literature review. Clin Biochem 2003;36:641–5. 4. Gillmore JD, Stangou AJ, Lachmann HJ, Goodman HJ, Wechalekar AD, Acheson J, Tennent GA, et al. Organ transplantation in hereditary apolipoprotein AI amyloidosis. Am J Transplant 2006;6: 2342–7. 5. Obici L, Bellotti V, Mangione P, Stoppini M, Arbustini E, Verga L, Zorzoli I, et al. The new apolipoprotein A-I variant leu(174) - -4gt; Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils
11.
12.
13.
14.
are constituted by the 93-residue N-terminal polypeptide. Am J Pathol 1999;155:695–702. Hamidi Asl K, Liepnieks JJ, Nakamura M, Parker F, Benson MD. A novel apolipoprotein A-1 variant, Arg173Pro, associated with cardiac and cutaneous amyloidosis. Biochem Biophys Res Commun 1999;257:584–8. Testro AG, Brennan SO, Macdonell RAL, Hawkins PN, Angus PW. Hereditary amyloidosis with progressive peripheral neuropathy associated with apolipoprotein AI Gly26Arg: outcome of hepatorenal transplantation. Liver Transpl 2007;13:1028–31. Booth DR, Tan SY, Booth SE, Tennent GA, Hutchinson WL, Hsuan JJ, Totty NF, et al. Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene. J Clin Invest 1996;97:2714–21. Caballerı´a J, Bruguera M, Sole´ M, Campistol JM, Rode´s J. Hepatic familial amyloidosis caused by a new mutation in the apolipoprotein AI gene: clinical and pathological features. Am J Gastroenterol 2001;96:1872–6. Coriu D, Dispenzieri A, Stevens FJ, Murphy CL, Wang S, Weiss DT, Solomon A. Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro. Amyloid 2003;10:215–23. Obici L, Palladini G, Giorgetti S, Bellotti V, Gregorini G, Arbustini E, Verga L, et al. Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families. Gastroenterology 2004;126:1416–22. Scalvini T, Martini PR, Gambera A, Tardanico R, Biasi L, Scolari F, Gregorini G, et al. Spermatogenic and steroidogenic impairment of the testicle characterizes the hereditary leucine-75proline apolipoprotein a-I amyloidosis. J Clin Endocrinol Metab 2008;93:1850–3. Sipe JD, Benson MD, Buxbaum JN, Ikeda S-I, Merlini G, Saraiva MJM, Westermark P. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 2012;19:167–70. Shaz BH, Lewis WD, Skinner M, Khettry U. Livers from patients with apolipoprotein A-I amyloidosis are not suitable as ‘‘domino’’ donors. Mod Pathol 2001;14:577–80.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
