Nodular regenerative hyperplasia
Synonyms and keywords: NRHL; Non-cirrhotic portal hypertension; NRH

# Overview
Nodular regenerative hyperplasia (NRH) is described as a rare form of non-cirrhotic portal hypertension in the absence of a recognizable cause. NRH is associated with solid organ transplant (eg. renal transplants, bone marrow transplants) and chronic use of medications. it may be classified into 2 subtypes: Pre-sinusoidal and sinusoidal. The pathogenesis of NRH is characterized by arterial hypervascularity secondary to loss of hepatic vein radicles and loss of central venule in the hepatic lobule. NRH is a rare disease. The estimated incidence of NRH is approximately 0.34 cases per 100,000 individuals. NRH is more commonly observed among patients between 25 and 65 years old. The majority of patients with NRH may be initially asymptomatic. Early clinical features include fatigue, weight loss, and abdominal distension.  If left untreated, the majority of patients with NRH may progress to develop acute hepatic failure and death. The diagnosis of NRH is made with the following diagnostic criteria: Latency of more than 6 months, minimal or no elevations in serum alanine transaminase (ALT), clinical, radiologic or endoscopic signs of portal hypertension, and liver biopsy. Treatment includes cessation of offending agents and management of portal hypertension and variceal bleeding.

# Historical Perspective
- In 1953, the first case of NRH was described by Ranstrom in a patient with Feltys syndrome, terming it as miliary hepatocellular adenomatatosis.
- NRH was first described by Steiner in 1959.

# Classification
- Nodular regenerative hyperplasia may be classified into 2 subtypes:
Pre-sinusoidal
Sinusoidal
- Pre-sinusoidal
- Sinusoidal
- Another variant of NRH may be included in Banti's syndrome, which is described as chronic splenic congestion chronic resulting in rapid destruction of red blood cells (RBCs) prematurely.

# Pathophysiology
- It is a poorly understood disease process thought to be mediated by chronic inflammatory and thrombotic processes leading to occlusion of hepatic microvascuature. Ischemic changes then lead to regeneration of hepatocytes.
- The pathogenesis of NRH is characterized by:
Arterial hypervascularity secondary to loss of hepatic vein radicles.
Loss of central venule in the hepatic lobule.
Diffuse regeneration of hepatocytes in the parenchyma in the form of nodules.
- Arterial hypervascularity secondary to loss of hepatic vein radicles.
- Loss of central venule in the hepatic lobule.
- Diffuse regeneration of hepatocytes in the parenchyma in the form of nodules.
- The RASSF1A gene has been associated with the development of NRH, involving the pro-apoptotic pathway.
- On gross pathology a diffuse nodularity may be seen.
- The most important findings on microscopic histopathological analysis:
Plates of hepatocytes in the parenchyma set in thick curved nodules.
"Plump" hepatocytes arranged in micronodules:
Central hyperplasia with an atrophic rim.
No fibrosis.
- Plates of hepatocytes in the parenchyma set in thick curved nodules.
- "Plump" hepatocytes arranged in micronodules:
Central hyperplasia with an atrophic rim.
- Central hyperplasia with an atrophic rim.
- No fibrosis.

# Causes
Common causes of NRH may include:
- Solid organ transplantation
- Autoimmune diseases
- Infections like HIV
- Hematological
- Neoplastic
- Chronic use of medications, such as:
Azathioprine 
Thioguanine
Mercaptopurine
Didanosine
Stavudine
Isoplatin
Vitamin A
Methotrexate
Trastuzumab
- Azathioprine 
- Thioguanine
- Mercaptopurine
- Didanosine
- Stavudine
- Isoplatin
- Vitamin A
- Methotrexate
- Trastuzumab
- NRH is commonly found in patients with Abernethys Syndrome.

# Differentiating nodular regenerative hyperplasia from other Diseases
- NRH must be differentiated from other diseases that cause fatigue, hematemesis, and weight-loss such as:
Hepatocellular carcinoma
Hepatic adenoma,
Focal nodular hyperplasia
Cirrhosis
Peptic ulcer
Schistosomiasis
Metastatic disease
- Hepatocellular carcinoma
- Hepatic adenoma,
- Focal nodular hyperplasia
- Cirrhosis
- Peptic ulcer
- Schistosomiasis
- Metastatic disease

# Epidemiology and Demographics
- NRH is a rare disease.
- The prevalence of NRH is approximately 31 cases per 100,000 individuals in the United Kingdom.
- The estimated incidence of NRH is approximately 0.34 cases per 100,000 individuals.

## Age
- More commonly observed among patients aged between 25 and 65 years old.
- More commonly observed among adults and elderly patients.

## Gender
- It affects men and women equally, however in patients receiving Azathioprine, a weak association has been reported with the male sex.

## Race
- There is no racial predilection for NRH.

# Risk Factors
- Common risk factors in the development of NRH include chronic vascular and infectious complications such as in:
Inflammatory bowel disease
Crohn's disease
Cystic fibrosis
Common variable immune deficiency (CVID)
Chronic granulomatous disease.
- Inflammatory bowel disease
- Crohn's disease
- Cystic fibrosis
- Common variable immune deficiency (CVID)
- Chronic granulomatous disease.
- Small bowel resection.

# Natural History, Complications and Prognosis
- Initially asymptomatic.
- An unexplained drop in platelets.
- Early clinical features include fatigue, weight loss, and abdominal distension.
- If left untreated, the majority of patients with nodular regenerative hyperplasia may progress to develop acute hepatic failure or liver decompensation and eventually requiring liver transplantation.
- Screening for the hepatocellular carcinoma is not recommended in these patients.
- NRH severity may be classified by the Child-Pugh score.
- Common complications of NRH, may include:
Portal hypertension
Variceal bleeding
Secondary peritonitis
Encephalopathy
- Portal hypertension
- Variceal bleeding
- Secondary peritonitis
- Encephalopathy
- The prognosis of NRH is related to the consequences of portal hypertension and the severity of the associated diseases.Prognosis is generally poor, and the mean survival rate of patients is approximately 8.1 years.

# Diagnosis

## Diagnostic Criteria
- The diagnosis of nodular regenerative hyperplasia is made with a strict diagnostic criteria, all of the following must be present:
Clinical, radiologic or endoscopic signs of portal hypertension, such as:
Ascites
Splenomegaly
Portovenous collaterals
Varices (esophageal or gastric)
Portal hypertensive gastropathy
Liver biopsy excluding cirrhosis; showing nodularity with minimal or no fibrosis. Presence of fibrous septa definitely excludes NRH.
Definite exclusion of all other causes of portal hypertension.
Confirmation of patent hepatic venous system on imaging.
- Clinical, radiologic or endoscopic signs of portal hypertension, such as:
Ascites
Splenomegaly
Portovenous collaterals
Varices (esophageal or gastric)
Portal hypertensive gastropathy
- Ascites
- Splenomegaly
- Portovenous collaterals
- Varices (esophageal or gastric)
- Portal hypertensive gastropathy
- Liver biopsy excluding cirrhosis; showing nodularity with minimal or no fibrosis. Presence of fibrous septa definitely excludes NRH.
- Definite exclusion of all other causes of portal hypertension.
- Confirmation of patent hepatic venous system on imaging.
- The diagnosis is favoured by:
Latency of more than 6 months of clinically associated drugs.
Minimal or no elevations in serum ALT (<120 U/L: <3 times ULN)
Alkaline phosphatase (<345 U/L: <3 times ULN)
- Latency of more than 6 months of clinically associated drugs.
- Minimal or no elevations in serum ALT (<120 U/L: <3 times ULN)
- Alkaline phosphatase (<345 U/L: <3 times ULN)

## Symptoms
- Symptoms of nodular regenerative hyperplasia may include the following:
Fatigue
Weight loss
Abdominal distension
Nausea
Hematemesis
- Fatigue
- Weight loss
- Abdominal distension
- Nausea
- Hematemesis

## Physical Examination
- Patients with NRH may be well-appearing, lethargic, or confused.
- Physical examination of the abdomen may be remarkable for:
Inspection
- Caput medusae
Appearance of distended and engorged superficial epigastric veins
- Appearance of distended and engorged superficial epigastric veins
Auscultation
- Positive liver scratch test for enlarged liver size.
- Cruveilhier-Baumgarten murmur
A venous hum in patients with portal hypertension
- A venous hum in patients with portal hypertension
Percussion
- Dull percussion
Palpation
- Abdominal distention
- Tenderness in right upper quadrant
- Hepatomegaly
- Splenomegaly
- Other physical signs for NRH may include:
- Pallor
- Jaundice
- Plantar and palmar erythema
- Dermatographic urticaria, or "scratching marks"
Muehrcke nails
Terry nails, or "luekonychia"
- Muehrcke nails
- Terry nails, or "luekonychia"

## Laboratory Findings
- Laboratory findings consistent with the diagnosis of NRH,  may include:
Anemia,Leucopenia and thrombocytopenia because of hypersplenism
Abnormal AST/ALT ratio
Less than <345 U/L: <3 times upper limit of normal
Decreased levels of vitamin B12
Liver biochemistry profile showing cholestasis, thought to be secondary to increased sinusoidal pressure.
- Anemia,Leucopenia and thrombocytopenia because of hypersplenism
- Abnormal AST/ALT ratio
Less than <345 U/L: <3 times upper limit of normal
- Less than <345 U/L: <3 times upper limit of normal
- Decreased levels of vitamin B12
- Liver biochemistry profile showing cholestasis, thought to be secondary to increased sinusoidal pressure.

## Imaging Findings
- Imaging studies useful for the diagnosis of NRH, may include:
Ultrasound (doppler U/S modality of choice)
CT scan
MRI scan
- Ultrasound (doppler U/S modality of choice)
- CT scan
- MRI scan
- On ultrasound:
May resemble the ring-shaped coral, an appearance first described in 2011.
Lesions usually smaller than 3mm
Round isoechoic or hypoechoic lesions
Thin hyper-echoic rim
- May resemble the ring-shaped coral, an appearance first described in 2011.
- Lesions usually smaller than 3mm
- Round isoechoic or hypoechoic lesions
- Thin hyper-echoic rim
- CT scan suggestive of nonspecific hypodense nodules without significant enhancement.
- MRI suggestive of Isointense nodules on T2-weighted images that contain foci of high intensity on T1-weighted images

## Other Diagnostic Studies
- NRH is definitely diagnosed using biopsy.
Findings include:
Diffuse fine nodularity of the liver
Nodule size between 1-3 mm
Mild hepatomegaly
- Findings include:
Diffuse fine nodularity of the liver
Nodule size between 1-3 mm
Mild hepatomegaly
- Diffuse fine nodularity of the liver
- Nodule size between 1-3 mm
- Mild hepatomegaly

# Treatment

## Medical Therapy
- There is no specific treatment for NRH.
- Mainstay therapy is preventing the progression of the disease (e.g., cessation of causative medication, treatment of the underlying conditions)  with acute management of complications, such as variceal bleeding. 
- Variceal bleeding in NRH can be treated in the same manner as variceal bleeding in cirrhotic portal hypertension by:
Use of non selective B blockers
Endoscopic variceal ligation
- Use of non selective B blockers
- Endoscopic variceal ligation

## Surgery
- Surgery is the mainstay of therapy for NRH in case of failure of endoscopic sclerotherapy/endoscopic variceal ligation. Other indication of surgery include symptomatic hypersplenism.
- TIPS is more suitable to treat and prevent refractory gastric variceal bleed in patients with NRH, however it is avoided in certain conditions such as:
Renal failure
Ascites
Promthrombic conditions like malignancy
Organ transplantation
- Renal failure
- Ascites
- Promthrombic conditions like malignancy
- Organ transplantation
- Surgical resection is usually performed for patients with persistent pain or for lesions that are suspicious on radiological findings.
- Splenectomy can be done if symptomatic hypersplenism.
- Liver transplantation is rarely considered.

## Prevention
- There are no primary preventive measures available for nodular regenerative hyperplasia, however close surveillance of the patient with the risk factors is required for the early diagnosis and management of the condition.
- In patients receiving neo-adjuvant (downstaging) therapy before resection of malignancy, it is generally recommended to keep the duration of chemotherapy to a minimum number of cycles.