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Year : 2016  |  Volume : 59  |  Issue : 3  |  Page : 413-416
Early cirrhosis in a young female with protein C deficiency: An extremely unusual case report with review

1 MD, DNB, PDCC Senior Histopathologist SRL Ltd, Fortis Hospital, Okhla, India
2 Associate Professor Pathology ILBS, New Delhi, India

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Date of Web Publication10-Aug-2016


Protein C deficiency is a well recognized risk factor for development of venous thromboembolism but has never been reported to be associated with development of liver cirrhosis .We report a case of a 26 years old female who presented with multiple thrombosis involving superior mesenteric vein ,main portal vein and multiple cerebral veins. Liver biopsy done was reported as cirrhosis possibly due to Wilson's disease. However no improvement was seen with D penicillamine and patient's condition detiorated. Further, work up of patient revealed absence of Protein C levels in the plasma. So finally the case was diagnosed as Cirrhosis liver with Protein C deficiency as the likely etiology. We conclude that Protein C deficiency should be investigated in patients with cirrhosis with thrombotic lesions of unknown etiology.

Keywords: Cirrhosis, protein C deficiency, thrombotic lesion

How to cite this article:
Bansal N, Bihari C. Early cirrhosis in a young female with protein C deficiency: An extremely unusual case report with review. Indian J Pathol Microbiol 2016;59:413-6

How to cite this URL:
Bansal N, Bihari C. Early cirrhosis in a young female with protein C deficiency: An extremely unusual case report with review. Indian J Pathol Microbiol [serial online] 2016 [cited 2022 Jan 20];59:413-6. Available from: https://www.ijpmonline.org/text.asp?2016/59/3/413/188119

   Introduction Top

Protein C is a Vitamin K-dependent zymogen synthesized in the liver.[1] It is activated by thrombin in complex with thrombomodulin.[2],[3] Activated protein C in turn inhibits activated factor V and VIII [4] and inhibits thrombin generation, thereby preventing uncontrolled thrombosis. Deficiency of protein C is a rare genetic trait with a high risk of thromboembolic disease.[5],[6],[7] In these patients, thrombin is not inactivated thus predisposing to increased thrombotic risks.

We report a case of a patient with protein C deficiency leading to portal vein thrombosis progressing rapidly to liver disease, with formation of a vicious cycle leading to early development of liver cirrhosis. To the best of our knowledge, no single case of cirrhosis secondary to protein C deficiency has been reported in the indexed English literature till date.

The knowledge of this entity is crucial for the practicing hepatologist as early diagnosis and timely anticoagulation therapy are rewarding in most patients.

   Case Report Top

We report a case of a 26-year-old female who was admitted to the emergency department of Institute of Liver and Biliary Sciences with complaints of off and on vomiting for the last 15–20 days followed by yellowish discoloration of urine and sclera. The patient also complained of altered sensorium for the past 4 days. There was no history of fever, hematemesis, or melena. The patient had a history of two episodes of upper gastrointestinal bleed 10 and 2 years back, for which esophageal variceal ligation was done each time. The patient also complained of abdominal distension associated with bilateral lower limb swelling 7 years back and for which she was diagnosed to have cirrhosis liver.

On examination, she was found to have icterus of 3+; pallor and pedal edema were present. Her abdomen was distended diffusely tender and liver was not palpable below costal margin. On central nervous system examination, she was conscious but not responding to commands, and rigidity of limb was present.

Laboratory investigations performed revealed hemolytic anemia with a positive direct Coomb's test and reticulocyte count of 3.4%. She also had thrombocytopenia and leukopenia. Her liver function test (LFT) was grossly deranged with a total serum bilirubin/direct/indirect of 41.42/21.98/19.44 mg/dl, aspartate aminotransferase/alanine transaminase - 518/213 IU/ml, serum alkaline phosphatase - 67 IU/ml, gamma glutamyl transferase - 45 IU/ml, serum albumin - 3 mg/dl, and globulin - 2.9 mg/dl. Results for test done for viral markers were negative. Autoimmune markers done antinuclear antibody, anti-smooth muscle antibodies, liver kidney microsomal LKM, and soluble liver antigen were all negative. Ascitic fluid examination revealed subacute bacterial peritonitis.

Computed tomography of the abdomen done showed chronic liver disease with cirrhotic changes with feature suggestive of portal hypertension. Bland thrombus involving superior mesenteric vein and main portal vein was also noted. All three major hepatic veins were patent [Figure 1].
Figure 1: Computed tomography scan showing chronic liver disease with cirrhotic changes with Bland thrombus in main portal vein and patent major hepatic veins

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With this clinical history of chronic liver disease with hemolytic anemia and limb rigidity, a provisional etiological diagnosis of Wilson's disease was considered and liver biopsy was done for same.

Liver biopsy showed distortion of acinar architecture with formation of regenerative parenchymal nodules intervened by intermediately thick fibrous septae. The periseptal hepatocytes show glycogenated nuclei and mildly increased copper deposits on rhodanine stain. The histological diagnosis was given as cirrhosis compatible with Wilson's disease [Figure 2].
Figure 2: (a) Histology showing cirrhotic liver (H and E, ×10). (b) Liver biopsy showing periseptal hepatocytes with glycogenated nuclei (H and E, ×20). (c) Liver biopsy showing cirrhotic liver (Masson's Trichrome [MAT], ×10)

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Workup for the same was done that showed a ceruloplasmin of 0.14, serum copper of 71.08 ug/dl, 24 h urinary copper of 85.75 mg/day, and dry weight liver copper assay in normal range. Her hepatic venous pressure gradient was 22 mmHg.

The patient condition did not improve over the days and plasmapheresis was done twice in view of highly deranged LFTs.

Further neurological opinion was sought and magnetic resonance imaging of the brain done showed acute infarct in bilateral cerebellum, left side of vermis, chronic infarct with gliosis in the left parietal lobe, and multiple lacunar infarcts in the bilateral ganglia capsular region and left anterior thalamus.

With the findings of multiple thrombosis, the patient was further worked up for coagulation parameters including protein S 111.8% (59–118), antithrombin III 16.5 (75–125%), and protein C 00 (70–140%), and factor V Leiden mutation was negative. Von willebrand factor was done and the level was 160% (60–210%). Hence, the patient was started on warfarin and Vitamin K and was finally diagnosed to have cirrhosis secondary to protein C deficiency.

   Discussion Top

Protein C deficiency is a rare autosomal recessive disorder. The incidence of asymptomatic protein C deficiency has been reported to be between 1 in 200 and 1 in 500 healthy individual, whereas the incidence of clinically significant protein C deficiency has been reported to be between 1 in 20,000.[8] Severe deficiency present in childhood as purpura fulminans and in adults as recurrent severe episodes of deep vein thrombosis, venous thromboembolism, disseminated intravascular coagulation, etc.

Protein C is a potent anticoagulant activated by thrombin with thrombomodulin and inhibits thrombin generation by inhibiting factor V and factor VIII involved in intrinsic and common pathway of coagulation [Figure 3].
Figure 3: Balance between procoagulant and anticoagulant in normal person

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Liver is involved in synthesis of multiple coagulant factors (anticoagulants and procoagulants) including factor II, V, VI, IX, X, XI, XIII, fibrinogen, protein C, and protein S. In patients of liver disease, there is decreased synthesis of all of these factors. Since there is a decrease in both anticoagulant and procoagulant factors, the delicate balance between the two is still maintained and coagulopathy is less likely [Figure 4]. However, the balance can be very easily altered in inherited or acquired deficiency of any of the coagulation factors, leading to a vicious cycle and rapid development of fibrosis as seen in our case.
Figure 4: Balance between procoagulant and anticoagulant is maintained in patients of liver disease

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In patients with protein C deficiency, factor V and VIII are not inhibited leading to an imbalance between anticoagulant and procoagulant leading to increased thrombotic tendencies.[9],[10],[11],[12],[13]

Involvement of liver secondary to protein C deficiency aggravates the imbalance between the anticoagulant and procoagulants, leading to early progression of cirrhosis in such patients [Figure 5]. During liver diseases, both anticoagulant and procoagulant are decreased; hence, a fine balance is maintained. However, inherited deficiency of protein C alters this thin balance and leads to hypercoagulability.
Figure 5: Protein C deficiency aggravates the imbalance between the anticoagulant and procoagulants leading to early progression of cirrhosis

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Protein C deficiency together with increased levels of Von Willebrand factor and factor VIII (secondary increased) aggravated the thrombotic risks and increased liver derangement as seen in our patient.

Choi et al. in a case report described that a patient with acute total occlusion of portal vein thrombus provoked by protein C and S deficiencies. The thrombus was completely recanalized with oral anticoagulant therapy.[9]

Yang et al. described two patients of portal vein thrombosis secondary to protein c deficiency.[10]

Increased copper deposits could be found in all chronic cholestatic disorders. Many such patients are misdiagnosed as Wilson disease as in our case where cholestatic pattern of injury might have led to falsely elevated hepatic copper. Similar findings are also reported by other authors of our institute on a series of four patients.[14]

Cirrhosis in prothrombotic states in usually seen in cases of Budd–Chiari syndrome which manifests as congested sinusoids and atrophic cords of hepatocytes. The fibrosis is usually venocentric starting from areas around the central vein. In our case, the patient had multiple infarcts in the brain; however, no thrombosis of major veins was found.

This case highlights the significance of protein C deficiency as a causative agent leading to liver cirrhosis. To the best of our knowledge, no such case has been reported in the indexed world literature till date. This entity should be thought of in cases of cryptogenic cirrhosis to prevent the dreaded complications as early diagnosis and timely anticoagulation therapy are rewarding in most patients.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Fair DS, Marlar RA. Biosynthesis and secretion of factor VII, protein C, protein S, and the protein C inhibitor from a human hepatoma cell line. Blood 1986;67:64-70.  Back to cited text no. 1
Owen WG, Esmon CT. Functional properties of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 1981;256:5532-5.  Back to cited text no. 2
Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci USA 1981;78:2249-52.  Back to cited text no. 3
Marlar RA, Kleiss AJ, Griffin JH. Human protein C: Inactivation of factors V and VIII in plasma by the activated molecule. Ann N Y Acad Sci 1981;370:303-10.  Back to cited text no. 4
Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-3.  Back to cited text no. 5
Bertina RM, Broekmans AW, van der Linden IK, Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemost 1982;48:1-5.  Back to cited text no. 6
Horellou MH, Conard J, Bertina RM, Samama M. Congenital protein C deficiency and thrombotic disease in nine French families. Br Med J (Clin Res Ed) 1984;289:1285-7.  Back to cited text no. 7
Dahlbäck B. The protein C anticoagulant system: Inherited defects as basis for venous thrombosis. Thromb Res 1995;77:1-43.  Back to cited text no. 8
Choi BK, Yang SH, Suh KH, Hwang JA, Lee MH, Si WK, et al. A case of portal vein thrombosis by protein C and S deficiency completely recanalized by anticoagulation therapy. Chonnam Med J 2011;47:185-8.  Back to cited text no. 9
Yang YY, Chan CC, Wang SS, Chiu CF, Hsu HC, Chiang JH, et al. Case report: Portal vein thrombosis associated with hereditary protein C deficiency: A report of two cases. J Gastroenterol Hepatol 1999;14:1119-23.  Back to cited text no. 10
Orozco H, Guraieb E, Takahashi T, Garcia-Tsao G, Hurtado R, Anaya R, et al. Deficiency of protein C in patients with portal vein thrombosis. Hepatology 1988;8:1110-1.  Back to cited text no. 11
Arav-Boger R, Reif S, Bujanover Y. Portal vein thrombosis caused by protein C and protein S deficiency associated with cytomegalovirus infection. J Pediatr 1995;126:586-8.  Back to cited text no. 12
Gameiro L, Pariente EA, Dupuis E, Gervais T, Viala JF, Trinh DH. Portal vein thrombosis and hereditary protein C deficiency. Presentation of a case and review of the literature. Gastroenterol Clin Biol 1992;16:177-81.  Back to cited text no. 13
Sood V, Rawat D, Khanna R, Alam S. Cholestatic liver disease masquerading as Wilson disease. Indian J Gastroenterol 2015;34:174-7.  Back to cited text no. 14

Correspondence Address:
Dr. Nalini Bansal
C6/18, 2nd Floor, Ardee City, Sector 52, Gurgaon, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.188119

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

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