A McNeill
Central Newcastle SHO Medical Rotation, Freeman Hospital and Royal Victoria Infirmary, Newcastle-upon-Tyne. United Kingdom.
Correspondance: 11 Broomieknowe Park, Bonnyrigg, Midlothian. Scotland. UK. EH19 2JB.
Email: Amcneill@doctors.org.uk
SMJ 2007 52(2): 56
Nodular regenerative hyperplasia (NRH) of the liver has been associated with a variety of autoimmune disorders; including Rheumatoid disease, CREST and diabetes mellitus. Here a case in which NRH presented concurrently with Graves’ disease is reported, and possible mechanisms for the association discussed.
A 57-year-old female was admitted with weight loss, confusion and abdominal distension. She gave a history of several months of severe anorexia to account for her weight loss, but reported no vomiting, abdominal pain, altered bowel habit or rectal bleeding. She had no past medical history other than that of a depressive disorder, and she took no regular medication. The patient did not drink alcohol to excess, smoke or misuse illicit substances. Physical examination revealed marked cachexia, fast atrial fibrillation and brisk reflexes. The JVP was elevated and a pan-systolic murmur radiating to the axilla was noted. There was a craggy right upper quadrant mass and shifting dullness. Marked bilateral proptosis and lid lag was also evident. There was a smooth goitre upon thyroid palpation. The initial impression was of hyperthyroidism and an occult malignancy.
Routine bloods demonstrated abnormal liver function (bilirubin 58, ALT 47, GGT 41, albumin 18), microcytic anaemia (haemoglobin 10 g/dL, MCV 85 fL, iron 8 umol/L) and hyperthyroidism (TSH <0.5, fT4 69 [range 8 – 27], fT3 5.3 [range 1 – 2.6]) with strongly positive thyroid receptor stimulating auto-antibodies (10 IU/L [range 0 – 1.5] and anti-thyroid peroxidase antibodies. Carcinoembryonic antigen was normal, while CA-125 was elevated (864 U/mL [range 0 – 35 U/mL]). Abdominal ultrasound revealed a shrunken, cirrhotic liver with ascites. A screen for infectious, autoimmune and metabolic causes of cirrhosis was negative. Anti-nuclear antibodies were positive at a titre of 1:40 with homogeneous nuclear staining. Upon aspiration the ascitic fluid was found to be a transudate which did not contain malignant cells. A CT scan of the abdomen was reported as showing liver cirrhosis with no intra-abdominal neoplasm or lymphadenopathy. As there was no malignancy, the elevated CA-125 was ascribed to hepatic cirrhosis. Upper gastrointestinal endoscopy excluded varices, but revealed a chronic duodenal ulcer to account for the iron deficiency anaemia. Echocardiography demonstrated moderate mitral regurgitation with severe pulmonary hypertension (PAP 64 mmHg). A CT pulmonary angiogram was performed, and excluded multiple pulmonary emboli as a cause of pulmonary hypertension. A diagnosis of primary pulmonary hypertension (PPH) was made.
Treatment for hyperthyroidism was initiated with carbimazole, while spironolactone and a low salt diet were commenced for treatment of ascites. Given the cryptogenic aetiology of the cirrhosis a transjugular liver biopsy was undertaken. Histological examination of the liver demonstrated only very mild fibrosis with no evidence of cirrhosis, while reticulin staining delineated a nodular outline to the liver parenchyma, consistent with nodular regenerative hyperplasia of the liver. Hepatic sinusoidal pressure was normal at 4 mmHg. Combined with the absence of varices and splenomegaly this effectively excluded portal hypertension and porto-pulmonary hypertension. As the patient had never been symptomatic of pulmonary hypertension, it was decided not to measure pulmonary wedge pressure. The patient’s clinical condition improved, her ascites resolved and she was discharged to outpatient care.
The association between portal hypertension and pulmonary hypertension in liver cirrhosis is well documented. However, only a handful of cases of pulmonary hypertension associated with portal hypertension in NRH have been reported.1, 2 Yutani et al and Bedossa et al each describe 2 cases with symptomatic pulmonary hypertension who were found to have portal hypertension and NRH at autopsy. The case reported in this paper is thus unusual as the patient had asymptomatic PPH and normal portal venous pressure. There are several theories to explain the association of portal and pulmonary hypertension in cirrhosis.3 In all theories explaining the aetiology of porto-pulmonary hypertension porto-caval shunts have a central role. It being variously proposed that they allow thrombi (thrombo-embolic theory), vasoconstrictors such as endothelin-1 (metabolic theory) or excessive blood volume (haemodynamic theory) to enter the pulmonary vasculature and induce hypertension.3 There was no clinical evidence of porto-systemic shunts in this case, thus it is possible that the association with pulmonary hypertension was coincidental. However, as pulmonary hypertension has been reported to precede portal hypertension in cirrhosis the NRH may have triggered PPH by an unknown mechanism.3.
NRH has been described in association with several autoimmune disorders, including Rheumatoid disease4, SLE5, CREST syndrome6, polyarteritis nodosa7 and diabetes mellitus.8 Here, an association between Grave’s disease and NRH is described for the first time. Whether the associations described between NRH and autoimmune conditions reflect chance occurrence or a common autoimmune pathogenesis is unclear. As NRH is proposed to be an autoimmune condition, associated with anti-phospholipid antibodies (anti-phospholipid antibodies were not assayed in this case), it is tempting to speculate that a single immunological defect leads to the production of multiple autoantibodies which induce both NRH and an auto-antibody mediated autoimmune disorder. This could explain the association of NRH and Grave’s disease in this case. In conclusion, this report adds to the literature describing porto-pulmonary hypertension in NRH, highlighting the fact that NRH can be associated with autoimmune disorders and that NRH is a non-malignant cause of elevated CA-125 levels.
Yutani C, Imakita M, Ishibashi-Ueda H, et al. Nodular regenerative hyperplasia of the liver associated with primary pulmonary hypertension. Hum Path 1988; 19: 726 – 731.
Bedossa P, Ngendayo L, Herve P, et al. Nodular regenerative hyperplasia and pulmonary arterial hypertension. Gastroenterol Clin Biol 1990; 14: 881 – 884.
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Kuramochi S, Tashiro Y, Torikata C, et al. Systemic lupus erythematosus associated with multiple nodular hyperplasia of the liver. Acta Pathol Jpn 1982; 32: 574.
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