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Hepatic amyloidosis presenting as intrahepatic cholestasis and portal hypertension: Case series and review of literature
Arab Journal of Gastroenterology 11 (2010) 167–170
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Case Report
Hepatic amyloidosis presenting as intrahepatic cholestasis and portal hypertension: Case series and review of literature Radha K. Yellapu *, Kiranmayi Yellapu, Choudhuri Gour Department of Gastroenterology, SGPGI, Lucknow, India
a r t i c l e
i n f o
Keywords: Hepatic amyloidosis Intrahepatic cholestasis Portal hypertension
a b s t r a c t Liver involvement in systemic amyloidosis is not uncommon; however, presentation with jaundice is rare. It is considered a preterminal sign. We present four cases of primary AL amyloidosis with severe intrahepatic cholestasis, two of whom presenting also with features of portal hypertension with oesophageal varices. Histopathology revealed diffuse hepatic amyloid deposits in the lobules, portal tracts and sinusoidal space. Review of literature reveals that hepatic amyloidosis presenting with cholestasis and portal hypertension is unusual and portends a poor prognosis. Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Amyloidosis is a heterogenous group of fibrillary protein deposition disorders involving the extracellular matrix of various organ systems. The liver is a major site of amyloid deposition. Hepatic involvement in amyloidosis can occur in both primary and secondary forms of the disease. Although liver is often involved, clinically apparent disease is rare. A mild elevation in serum alkaline phosphatase level and hepatomegaly are the most common findings. Jaundice is reported in less than 5% in the literature. We present four cases of hepatic amyloidosis presenting as severe intrahepatic cholestasis, two of whom having also portal hypertension. Case reports Patient 1 A 55-year-old man was admitted in May 2003 with worsening abdominal distension for 1 month. He had anorexia, weight loss of 10 kg for 6 months and progressive jaundice with pruritus for 3 months. He had no history of alcohol intake or other risk factors for liver disease. Clinical examination showed scleral icterus, a firm hepatomegaly measuring 18 cm at the right midclavicular line, mild splenomegaly and moderate ascites. Results of laboratory tests are given in Table 1. He had 2 g/day proteinuria and elevated serum creatinine (4.1 mg/dl). No M band was detected in serum or urine electrophoresis. Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr virus and herpes virus markers were * Corresponding author. Address: Department of Liver Medicine, Mount Sinai Medical Center, NY 10029, United States. Tel.: +1 646 709 4486. E-mail addresses: [email protected], [email protected] (R.K. Yellapu).
negative. Autoimmune markers were negative, and serum ferritin was not elevated. Abdominal ultrasound showed a homogenous enlarged liver with coarse echotexture, dilated portal vein, mild splenomegaly and ascites suggestive of portal hypertension. He had patent portal and hepatic veins. Endoscopy showed two columns of grade 2 oesophageal varices. Ultrasound guided percutaneous liver biopsy revealed diffuse effacement of lobular architecture and sinusoidal spaces were filled with amorphous, eosinophilic, hyaline material suggestive of amyloid deposits (Fig. 1). The deposited material was congophilic and resistant to potassium permanganate treatment. There were no obvious causes of secondary amyloidosis or features of multiple myeloma. Primary amyloidosis with predominant hepatic involvement was diagnosed. During hospital stay he had worsening renal failure, sepsis, gastrointestinal bleeding and preterminally had arrhythmia. He died 18 days after admission to hospital. Patient 2 A 75-year-old man was admitted to hospital in January 2004 for progressive jaundice with pruritus and significant anorexia of 3 months duration. He denied alcohol intake and other risk factors of liver disease. Clinical examination showed scleral icterus, lower limb oedema and firm hepatomegaly measuring 19 cm at the right midclavicular line. There was neither splenomegaly nor ascites. Results of laboratory tests are given in Table 1. He had 1.2 g/day proteinuria and elevated serum creatinine (1.8 mg/dl). An M band (IgA Kappa) was detected in serum and kappa light chains in urine electrophoresis. Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr virus and herpes virus markers were negative. Autoimmune markers were negative and serum ferritin was normal. Abdominal ultrasound showed a homogenous enlarged liver with patent portal and
1687-1979/$ - see front matter Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ajg.2010.07.007
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Table 1 Liver function tests. Patient
Serum bilirubin, mg/dl
Alkaline phosphatase, IU/L
AST, IU/L
ALT, IU/L
Prothrombin time (control), s
Serum albumin, g/dl
1 2 3 4
6.2 9.6 7.9 11.6
2856 1219 1402 1642
90 99 51 120
60 69 186 117
15.6 14.9 15.8 15.6
2.6 2.8 2.0 1.9
(12.2) (12.1) (12.0) (11.4)
Normal range values: Serum bilirubin 0.5–1.0 mg/dl, alkaline phosphatase: 30–120 IU/L, AST: 25–35 IU/L, ALT: 25-35 IU/L, serum albumin: 4–6 g/dl.
hepatic veins. Endoscopy showed no oesophageal varices. Submucosal deposits of amyloid were found in duodenal biopsy (Fig. 2). Percutaneous liver biopsy revealed diffuse and massive perisinusoidal amyloid deposits. There were no obvious causes of secondary amyloidosis or features of multiple myeloma. Primary AL amyloidosis with predominant hepatic involvement was diagnosed. He had sudden death during hospital stay secondary to massive aspiration. Patient 3 A 60-year-old man was admitted in May 2007 with worsening abdominal distension for 2 month. He had anorexia, generalized weakness for 4 months and progressive jaundice with pruritus for 2 months. He had no history of significant alcohol intake or other risk factors for liver disease. Clinical examination showed scleral icterus, lower limb oedema, hepatomegaly measuring 16 cm at the right midclavicular line, mild splenomegaly and moderate ascites. Results of liver tests are given in Table 1. He had 3 g/ day proteinuria. No M band was detected neither in serum nor in urine during electrophoresis. Urinary Bence Jones proteins were negative. Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr Virus and herpes virus markers were negative. Autoimmune markers were negative, and serum ferritin was normal. Abdominal ultrasound showed a homogenous enlarged liver with coarse echotexture, dilated portal vein, mild splenomegaly and ascites suggestive of portal hypertension. He had patent portal and hepatic veins. Endoscopy showed four columns of grade 2 oesophageal varices and mid portal hypertensive gastropathy. Duodenal biopsy showed submucosal and mucosal vessels displaying deposition of acellular pale eosinophilic congophilic material with apple green birefringence under polarized light suggestive of amyloidosis. Bone marrow biopsy showed infiltration with ma-
Fig. 1. Liver biopsy 1: Sinusoidal spaces are filled with an eosinophilic amorphous material (arrows). The hepatocytes flanking the sinusoids are compressed and atrophic (arrow heads). Note also that the portal tract on the left of the field appears compressed. Bile ducts were normal, with no ductular reaction (H&E stain, original magnification 100).
ture plasmocytes bearing IgA with lambda light chains and interstitial deposits of amyloid. There were no obvious causes of secondary amyloidosis or features of multiple myeloma. Primary AL amyloidosis with predominant hepatic and renal involvement was diagnosed. The patient received supportive treatment only and died from sepsis and gastrointestinal bleeding 1 month after admission.
Patient 4 A 63-year-old man was admitted to hospital in August 2006 for progressive jaundice with pruritus of 3 months and significant anorexia of 6 months duration. He denied alcohol intake and other risk factors of liver disease. Clinical examination showed scleral icterus, firm hepatomegaly measuring 18 cm at the right midclavicular line. There was neither splenomegaly nor ascites. Results of laboratory tests are given in Table 1. He had 1.2 g/day proteinuria and elevated serum creatinine (1.8 mg/dl). Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr virus and herpes virus markers were negative. Autoimmune markers were negative, and serum ferritin was normal. Abdominal ultrasound showed a homogenous enlarged liver with patent portal and hepatic veins. Percutaneous liver biopsy revealed diffuse deposition of an amorphous substance plugging mostly the sinusoids, resulting in atrophy and dropout of hepatocytes suggestive of amyloid deposits (Fig. 3). Rectal biopsy and abdominal fat pad biopsy were negative. Bone marrow biopsy showed mild plasmacytosis of 6–8%, without amyloid deposits. An M component (IgG lambda) was positive in serum and lambda light chains in urine electrophoresis. He had no features of myeloma. Primary AL amyloidosis with predominant hepatic involvement was diagnosed. He died with urinary tract infection, sepsis and renal failure after 3 months of admission.
Fig. 2. Duodenal biopsy: Duodenal mucosa showing the presence of an eosinophilic amorphous material in the lamina propria as well as in the submucosa (arrows) (H&E stain, original magnification 100).
R.K. Yellapu et al. / Arab Journal of Gastroenterology 11 (2010) 167–170
Fig. 3. Liver biopsy 2: Diffuse deposition of an amorphous substance plugging mostly the sinusoids, resulting in atrophy and dropout of hepatocytes. Part of a portal tract is shown and demonstrates mild ductular reaction (arrow) (H&E stain, original magnification 100).
Discussion Amyloidosis is not a single disease, but a series of diseases in which there is extracellular deposition of a protein, often leading to prominent end organ dysfunction. Hepatic involvement is a well-recognized feature of both primary AL and secondary AA type of systemic amyloidosis. It is present in 62–90% with AL amyloidosis, 22–43% with multiple myeloma-associated amyloidosis, and 59–60% with AA amyloidosis [1]. Hepatomegaly (57–83%) and elevated alkaline phosphatase level are the common clinical presentations. Hyperbilirubinemia is found in only 5% of patients and is associated with a poor prognosis [2]. Cholestatic jaundice and portal hypertension are extremely rare presentations of hepatic amyloidosis. A review of literature revealed that there were 46 patients, including our four patients, with hepatic amyloidosis manifesting as severe intrahepatic cholestasis. Of these 46 patients, 32 were men, and 14 were women, and the median age was 63 (range 29–85) years. Forty-four patients had primary AL amyloid deposits, and only two patients had secondary AA amyloidosis. Clinical features were hepatomegaly in 89%, ascites in 51%, pruritus in 39%, splenomegaly in 30% and gastrointestinal bleeding in 17% of cases. The median value of serum ALT was 58 (range 18–194) U/l, of bilirubin was 11.8 (range 2.5–43.9), and of ALP was 1385 (range 243– 2856) U/l, albumin was 2.2(range 1.2–3.2), prothrombin time 3.2 (range 2.8–5.4) s. The prognosis in these cholestatic patients is worse (mean survival of 3 months) than that reported in other patients with amyloidosis. Of the total 46 patients in our review of cases, the major cause of death was renal failure in 58%, other causes being cardiac failure (14%), liver failure (18%), gastrointestinal bleeding and sepsis (10%) [3–6]. The pathogenesis of cholestasis in hepatic amyloidosis is due to the compression of the intrahepatic bile ducts by amyloid deposits predominately in the portal area and sinusoidal space. Majority of patients reported had striking replacement of the liver parenchyma by amyloid, leading to pressure atrophy of hepatocytes with resultant cord-like islands of hepatocytes [7]. Proliferation of small bile ducts, centrilobular cholestasis and bile thrombi are also frequently reported. Obstructive jaundice is reported by amyloid deposition in the extrahepatic and large intrahepatic bile ducts; however, none of the patients reviewed had this form of obstructive jaundice. The risk of bleeding with liver biopsies is controversial. Some investigators report an increased risk of haemorrhage, while others claim that liver biopsies are safe [2,3,8].
169
Ultrasound and computed tomography scan findings in these patients with intrahepatic cholestasis are non-specific. Magnetic resonance imaging with oral manganese containing contrast agent shows several focal areas without contrast uptake in the hepatocytes and no bile excretion after 8 h [9]. Portal hypertension is an uncommon presentation of hepatic amyloidosis. So far less than 20 patients are described with this presentation [10–12]. Majority of these cases are seen in the setting of primary AL amyloidosis; however, there are reports in secondary AA amyloidosis as well. Oesophageal varices were demonstrated in 12 patients, with eight patients presenting with gastrointestinal bleeding from ruptured oesophageal varices. Although portal pressures have only been measured in five patients, there appears no direct correlation between the degree of elevation and the presence of varices or risk of gastrointestinal bleeding. This could be explained by a mild increase in portal pressure, which does not allow collateral circulation, and the rapid deterioration of these patients precludes the development of varices. Further, in these patients of hepatic amyloidosis, abnormal clotting factors, increased vessel permeability or impaired contractility and ulceration of the gastrointestinal tract due to amyloid infiltration contribute to gastrointestinal bleeding [13]. Portal hypertension in hepatic amyloidosis is of sinusoidal type. Sinusoidal portal hypertension is secondary to the reduction in the vascular space of hepatic sinusoids by amyloid deposits in the space of Disse [10]. Hepatic histology in these patients often shows massive intralobular amyloid deposition causing sinusoidal obstruction and surrounding compression atrophy of hepatocytes. Centrilobular vein lesions, periportal fibrosis or regenerating nodules are usually absent. The morphological differences in the pattern of amyloid infiltration in primary and secondary amyloidosis may explain why portal hypertension develops mostly in patients with primary hepatic amyloidosis. Portal hypertension contributes to ascites seen in these patients, other common factors responsible being hypoalbuminemia due to nephritic syndrome and cardiac failure. Combination of portal hypertension and severe intrahepatic cholestasis is rare, only six cases are reported in the literature [14,15]. Two of our patients had this rare combination of severe jaundice and portal hypertension. Prognosis is universally poor, with gastrointestinal bleeding being the common cause of death. The treatment of patients with cholestatic amyloidosis and portal hypertension has been dismal and predominantly supportive. There are only three reports of liver transplantation for primary hepatic amyloidosis [16,17]. In one case, sequential liver and stem cell transplantation led to the resolution of disease [18]. Ursodeoxycholic acid has been shown to decrease alkaline phosphatase and gamma-glutamyl transferase [19]. Recently, there have been encouraging results with high dose chemotherapy and haematopoietic stem cell transplantation in selective AL amyloidosis. We suggest that, hepatic amyloidosis should be considered in the differential diagnosis of unexplained intrahepatic cholestasis and non-cirrhotic portal hypertension. Conflicts of interest The authors declared that there was no conflict of interest. References [1] Levine RA. Amyloid disease of the liver: correlation of clinical, functional, and morphological features in forty seven patients. Am J Med 1962;33:349–57. [2] Gertz MA, Kyle RA. Hepatic amyloidosis: clinical appraisal in 77 patients. Hepatology 1997;25:118–21. [3] Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA. Primary (AL) hepatic amyloidosis, clinical features and natural history in 98 patients. Medicine 2003;82:291–8. [4] Lovat LB, Persey MR, Madhoo S, Pepys MB, Hawkins PN. The liver in systemic amyloidosis: insights from 123I serum amyloid P component scintigraphy in 484 patients. Gut 1998;42:727–34.
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[5] Rockey DC, Durham NC. Striking cholestatic liver disease: a distinct manifestation of advanced primary amyloidosis. South Med J 1999;92:236–41. [6] Liu CJ, Chien RN, Huang SF, Chiang JM. Severe intrahepatic cholestasis in an elderly patient with primary amyloidosis and colon adenocarcinoma. Chang Gung Med J 2004;27:74–9. [7] Rubinow A, Koff RS, Cohen AS. Severe intrahepatic cholestasis in primary amyloidosis. A report of four cases and a review of the literature. Am J Med 1978;64:937–46. [8] Harrison RF, Hawkins PN, Roche WR, Mac Mohan RF, Hubscher SG, Buckels JA. ‘‘Fragile” liver and massive hepatic hemorrhage due to hereditary amyloidosis. Gut 1996;38:151–2. [9] Moller JM, Santoni-Rugiu E, Chabanova E, Logager V, Hansen AB, Thomsen HS. Magnetic resonance imaging with liver-specific contrast agent in primary amyloidosis and intrahepatic cholestasis. Acta Radiol 2007;48:145–9. [10] Bion E, Brenard R, Pariente EA, Lebrec D, Degott C, Maitre F, et al. Sinusoidal portal hypertension in hepatic amyloidosis. Gut 1991;32:227–30. [11] Itescu S. Hepatic amyloidosis an unusual cause of ascites and portal hypertension. Arch Intern Med 1984;144:2257–9. [12] Mainenti PP, Patrelli G, Lamanda R, Amalfi G, Castiglione F. Primary systemic amyloidosis with giant hepatomegaly and a swiftly progressive course. J Clin Gastroenterol 1997;24:173–5.
[13] Ebert EC, Nagar M. Gastrointestinal manifestations of amyloidosis. Am J Gastroenterol 2008;103:776–87. [14] Zeijen RN, Sels JP, Flendrig JA, Arends JW. Portal hypertension and intrahepatic cholestasis in hepatic amyloidosis. Neth J Med 1991;38:257–61. [15] Dorde Culafic, Mirjana Perisic, Boricic I, Culafic-Vojinovic V, Vukcevic M. Primary amyloidosis presenting with cholestasis and hyperkinetic portal hypertension. J Gastrointestinal Liver Dis 2007;16:201–4. [16] Novak G, Westermark P, Wernerson A, Herlenius G, Sletten K, Ericzon B. Liver transplantation as a rescue treatment in a patient with primary AL kappa amyloidosis. Transpl Int 2000;13:92–7. [17] Sandberg-Gertzen H, Ericzon B, Blomberg B. Primary amyloidosis with spontaneous splenic rupture, cholestasis and liver failure treated with emergency liver transplantation. Am J Gastroenterol 1998;93:2254–6. [18] Kumar KS, Lefkowitch J, Russo MW, Hesdorffer C, Kinkhabwala M, Kapur S, et al. Successful sequential liver and stem cell transplantation for hepatic failure due to primary AL amyloidosis. Gastroenterology 2002;122: 2026–31. [19] Faust D, Akoglu B, Ristic G, Milovic V. Ursodeoxycholic acid for treatment of cholestasis in patients with hepatic amyloidosis. Scand J Gastroenterol. 2008;43:375–9.
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Case Report
Hepatic amyloidosis presenting as intrahepatic cholestasis and portal hypertension: Case series and review of literature Radha K. Yellapu *, Kiranmayi Yellapu, Choudhuri Gour Department of Gastroenterology, SGPGI, Lucknow, India
a r t i c l e
i n f o
Keywords: Hepatic amyloidosis Intrahepatic cholestasis Portal hypertension
a b s t r a c t Liver involvement in systemic amyloidosis is not uncommon; however, presentation with jaundice is rare. It is considered a preterminal sign. We present four cases of primary AL amyloidosis with severe intrahepatic cholestasis, two of whom presenting also with features of portal hypertension with oesophageal varices. Histopathology revealed diffuse hepatic amyloid deposits in the lobules, portal tracts and sinusoidal space. Review of literature reveals that hepatic amyloidosis presenting with cholestasis and portal hypertension is unusual and portends a poor prognosis. Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Amyloidosis is a heterogenous group of fibrillary protein deposition disorders involving the extracellular matrix of various organ systems. The liver is a major site of amyloid deposition. Hepatic involvement in amyloidosis can occur in both primary and secondary forms of the disease. Although liver is often involved, clinically apparent disease is rare. A mild elevation in serum alkaline phosphatase level and hepatomegaly are the most common findings. Jaundice is reported in less than 5% in the literature. We present four cases of hepatic amyloidosis presenting as severe intrahepatic cholestasis, two of whom having also portal hypertension. Case reports Patient 1 A 55-year-old man was admitted in May 2003 with worsening abdominal distension for 1 month. He had anorexia, weight loss of 10 kg for 6 months and progressive jaundice with pruritus for 3 months. He had no history of alcohol intake or other risk factors for liver disease. Clinical examination showed scleral icterus, a firm hepatomegaly measuring 18 cm at the right midclavicular line, mild splenomegaly and moderate ascites. Results of laboratory tests are given in Table 1. He had 2 g/day proteinuria and elevated serum creatinine (4.1 mg/dl). No M band was detected in serum or urine electrophoresis. Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr virus and herpes virus markers were * Corresponding author. Address: Department of Liver Medicine, Mount Sinai Medical Center, NY 10029, United States. Tel.: +1 646 709 4486. E-mail addresses: [email protected], [email protected] (R.K. Yellapu).
negative. Autoimmune markers were negative, and serum ferritin was not elevated. Abdominal ultrasound showed a homogenous enlarged liver with coarse echotexture, dilated portal vein, mild splenomegaly and ascites suggestive of portal hypertension. He had patent portal and hepatic veins. Endoscopy showed two columns of grade 2 oesophageal varices. Ultrasound guided percutaneous liver biopsy revealed diffuse effacement of lobular architecture and sinusoidal spaces were filled with amorphous, eosinophilic, hyaline material suggestive of amyloid deposits (Fig. 1). The deposited material was congophilic and resistant to potassium permanganate treatment. There were no obvious causes of secondary amyloidosis or features of multiple myeloma. Primary amyloidosis with predominant hepatic involvement was diagnosed. During hospital stay he had worsening renal failure, sepsis, gastrointestinal bleeding and preterminally had arrhythmia. He died 18 days after admission to hospital. Patient 2 A 75-year-old man was admitted to hospital in January 2004 for progressive jaundice with pruritus and significant anorexia of 3 months duration. He denied alcohol intake and other risk factors of liver disease. Clinical examination showed scleral icterus, lower limb oedema and firm hepatomegaly measuring 19 cm at the right midclavicular line. There was neither splenomegaly nor ascites. Results of laboratory tests are given in Table 1. He had 1.2 g/day proteinuria and elevated serum creatinine (1.8 mg/dl). An M band (IgA Kappa) was detected in serum and kappa light chains in urine electrophoresis. Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr virus and herpes virus markers were negative. Autoimmune markers were negative and serum ferritin was normal. Abdominal ultrasound showed a homogenous enlarged liver with patent portal and
1687-1979/$ - see front matter Ó 2010 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ajg.2010.07.007
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Table 1 Liver function tests. Patient
Serum bilirubin, mg/dl
Alkaline phosphatase, IU/L
AST, IU/L
ALT, IU/L
Prothrombin time (control), s
Serum albumin, g/dl
1 2 3 4
6.2 9.6 7.9 11.6
2856 1219 1402 1642
90 99 51 120
60 69 186 117
15.6 14.9 15.8 15.6
2.6 2.8 2.0 1.9
(12.2) (12.1) (12.0) (11.4)
Normal range values: Serum bilirubin 0.5–1.0 mg/dl, alkaline phosphatase: 30–120 IU/L, AST: 25–35 IU/L, ALT: 25-35 IU/L, serum albumin: 4–6 g/dl.
hepatic veins. Endoscopy showed no oesophageal varices. Submucosal deposits of amyloid were found in duodenal biopsy (Fig. 2). Percutaneous liver biopsy revealed diffuse and massive perisinusoidal amyloid deposits. There were no obvious causes of secondary amyloidosis or features of multiple myeloma. Primary AL amyloidosis with predominant hepatic involvement was diagnosed. He had sudden death during hospital stay secondary to massive aspiration. Patient 3 A 60-year-old man was admitted in May 2007 with worsening abdominal distension for 2 month. He had anorexia, generalized weakness for 4 months and progressive jaundice with pruritus for 2 months. He had no history of significant alcohol intake or other risk factors for liver disease. Clinical examination showed scleral icterus, lower limb oedema, hepatomegaly measuring 16 cm at the right midclavicular line, mild splenomegaly and moderate ascites. Results of liver tests are given in Table 1. He had 3 g/ day proteinuria. No M band was detected neither in serum nor in urine during electrophoresis. Urinary Bence Jones proteins were negative. Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr Virus and herpes virus markers were negative. Autoimmune markers were negative, and serum ferritin was normal. Abdominal ultrasound showed a homogenous enlarged liver with coarse echotexture, dilated portal vein, mild splenomegaly and ascites suggestive of portal hypertension. He had patent portal and hepatic veins. Endoscopy showed four columns of grade 2 oesophageal varices and mid portal hypertensive gastropathy. Duodenal biopsy showed submucosal and mucosal vessels displaying deposition of acellular pale eosinophilic congophilic material with apple green birefringence under polarized light suggestive of amyloidosis. Bone marrow biopsy showed infiltration with ma-
Fig. 1. Liver biopsy 1: Sinusoidal spaces are filled with an eosinophilic amorphous material (arrows). The hepatocytes flanking the sinusoids are compressed and atrophic (arrow heads). Note also that the portal tract on the left of the field appears compressed. Bile ducts were normal, with no ductular reaction (H&E stain, original magnification 100).
ture plasmocytes bearing IgA with lambda light chains and interstitial deposits of amyloid. There were no obvious causes of secondary amyloidosis or features of multiple myeloma. Primary AL amyloidosis with predominant hepatic and renal involvement was diagnosed. The patient received supportive treatment only and died from sepsis and gastrointestinal bleeding 1 month after admission.
Patient 4 A 63-year-old man was admitted to hospital in August 2006 for progressive jaundice with pruritus of 3 months and significant anorexia of 6 months duration. He denied alcohol intake and other risk factors of liver disease. Clinical examination showed scleral icterus, firm hepatomegaly measuring 18 cm at the right midclavicular line. There was neither splenomegaly nor ascites. Results of laboratory tests are given in Table 1. He had 1.2 g/day proteinuria and elevated serum creatinine (1.8 mg/dl). Viral markers for Hepatitis A, B, C, E and cytomegalovirus, Ebstein barr virus and herpes virus markers were negative. Autoimmune markers were negative, and serum ferritin was normal. Abdominal ultrasound showed a homogenous enlarged liver with patent portal and hepatic veins. Percutaneous liver biopsy revealed diffuse deposition of an amorphous substance plugging mostly the sinusoids, resulting in atrophy and dropout of hepatocytes suggestive of amyloid deposits (Fig. 3). Rectal biopsy and abdominal fat pad biopsy were negative. Bone marrow biopsy showed mild plasmacytosis of 6–8%, without amyloid deposits. An M component (IgG lambda) was positive in serum and lambda light chains in urine electrophoresis. He had no features of myeloma. Primary AL amyloidosis with predominant hepatic involvement was diagnosed. He died with urinary tract infection, sepsis and renal failure after 3 months of admission.
Fig. 2. Duodenal biopsy: Duodenal mucosa showing the presence of an eosinophilic amorphous material in the lamina propria as well as in the submucosa (arrows) (H&E stain, original magnification 100).
R.K. Yellapu et al. / Arab Journal of Gastroenterology 11 (2010) 167–170
Fig. 3. Liver biopsy 2: Diffuse deposition of an amorphous substance plugging mostly the sinusoids, resulting in atrophy and dropout of hepatocytes. Part of a portal tract is shown and demonstrates mild ductular reaction (arrow) (H&E stain, original magnification 100).
Discussion Amyloidosis is not a single disease, but a series of diseases in which there is extracellular deposition of a protein, often leading to prominent end organ dysfunction. Hepatic involvement is a well-recognized feature of both primary AL and secondary AA type of systemic amyloidosis. It is present in 62–90% with AL amyloidosis, 22–43% with multiple myeloma-associated amyloidosis, and 59–60% with AA amyloidosis [1]. Hepatomegaly (57–83%) and elevated alkaline phosphatase level are the common clinical presentations. Hyperbilirubinemia is found in only 5% of patients and is associated with a poor prognosis [2]. Cholestatic jaundice and portal hypertension are extremely rare presentations of hepatic amyloidosis. A review of literature revealed that there were 46 patients, including our four patients, with hepatic amyloidosis manifesting as severe intrahepatic cholestasis. Of these 46 patients, 32 were men, and 14 were women, and the median age was 63 (range 29–85) years. Forty-four patients had primary AL amyloid deposits, and only two patients had secondary AA amyloidosis. Clinical features were hepatomegaly in 89%, ascites in 51%, pruritus in 39%, splenomegaly in 30% and gastrointestinal bleeding in 17% of cases. The median value of serum ALT was 58 (range 18–194) U/l, of bilirubin was 11.8 (range 2.5–43.9), and of ALP was 1385 (range 243– 2856) U/l, albumin was 2.2(range 1.2–3.2), prothrombin time 3.2 (range 2.8–5.4) s. The prognosis in these cholestatic patients is worse (mean survival of 3 months) than that reported in other patients with amyloidosis. Of the total 46 patients in our review of cases, the major cause of death was renal failure in 58%, other causes being cardiac failure (14%), liver failure (18%), gastrointestinal bleeding and sepsis (10%) [3–6]. The pathogenesis of cholestasis in hepatic amyloidosis is due to the compression of the intrahepatic bile ducts by amyloid deposits predominately in the portal area and sinusoidal space. Majority of patients reported had striking replacement of the liver parenchyma by amyloid, leading to pressure atrophy of hepatocytes with resultant cord-like islands of hepatocytes [7]. Proliferation of small bile ducts, centrilobular cholestasis and bile thrombi are also frequently reported. Obstructive jaundice is reported by amyloid deposition in the extrahepatic and large intrahepatic bile ducts; however, none of the patients reviewed had this form of obstructive jaundice. The risk of bleeding with liver biopsies is controversial. Some investigators report an increased risk of haemorrhage, while others claim that liver biopsies are safe [2,3,8].
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Ultrasound and computed tomography scan findings in these patients with intrahepatic cholestasis are non-specific. Magnetic resonance imaging with oral manganese containing contrast agent shows several focal areas without contrast uptake in the hepatocytes and no bile excretion after 8 h [9]. Portal hypertension is an uncommon presentation of hepatic amyloidosis. So far less than 20 patients are described with this presentation [10–12]. Majority of these cases are seen in the setting of primary AL amyloidosis; however, there are reports in secondary AA amyloidosis as well. Oesophageal varices were demonstrated in 12 patients, with eight patients presenting with gastrointestinal bleeding from ruptured oesophageal varices. Although portal pressures have only been measured in five patients, there appears no direct correlation between the degree of elevation and the presence of varices or risk of gastrointestinal bleeding. This could be explained by a mild increase in portal pressure, which does not allow collateral circulation, and the rapid deterioration of these patients precludes the development of varices. Further, in these patients of hepatic amyloidosis, abnormal clotting factors, increased vessel permeability or impaired contractility and ulceration of the gastrointestinal tract due to amyloid infiltration contribute to gastrointestinal bleeding [13]. Portal hypertension in hepatic amyloidosis is of sinusoidal type. Sinusoidal portal hypertension is secondary to the reduction in the vascular space of hepatic sinusoids by amyloid deposits in the space of Disse [10]. Hepatic histology in these patients often shows massive intralobular amyloid deposition causing sinusoidal obstruction and surrounding compression atrophy of hepatocytes. Centrilobular vein lesions, periportal fibrosis or regenerating nodules are usually absent. The morphological differences in the pattern of amyloid infiltration in primary and secondary amyloidosis may explain why portal hypertension develops mostly in patients with primary hepatic amyloidosis. Portal hypertension contributes to ascites seen in these patients, other common factors responsible being hypoalbuminemia due to nephritic syndrome and cardiac failure. Combination of portal hypertension and severe intrahepatic cholestasis is rare, only six cases are reported in the literature [14,15]. Two of our patients had this rare combination of severe jaundice and portal hypertension. Prognosis is universally poor, with gastrointestinal bleeding being the common cause of death. The treatment of patients with cholestatic amyloidosis and portal hypertension has been dismal and predominantly supportive. There are only three reports of liver transplantation for primary hepatic amyloidosis [16,17]. In one case, sequential liver and stem cell transplantation led to the resolution of disease [18]. Ursodeoxycholic acid has been shown to decrease alkaline phosphatase and gamma-glutamyl transferase [19]. Recently, there have been encouraging results with high dose chemotherapy and haematopoietic stem cell transplantation in selective AL amyloidosis. We suggest that, hepatic amyloidosis should be considered in the differential diagnosis of unexplained intrahepatic cholestasis and non-cirrhotic portal hypertension. Conflicts of interest The authors declared that there was no conflict of interest. References [1] Levine RA. Amyloid disease of the liver: correlation of clinical, functional, and morphological features in forty seven patients. Am J Med 1962;33:349–57. [2] Gertz MA, Kyle RA. Hepatic amyloidosis: clinical appraisal in 77 patients. Hepatology 1997;25:118–21. [3] Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA. Primary (AL) hepatic amyloidosis, clinical features and natural history in 98 patients. Medicine 2003;82:291–8. [4] Lovat LB, Persey MR, Madhoo S, Pepys MB, Hawkins PN. The liver in systemic amyloidosis: insights from 123I serum amyloid P component scintigraphy in 484 patients. Gut 1998;42:727–34.
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