Hers Disease - An Overview

What Is Hers Disease?

The liver and skeletal muscles are the sites for glycogen storage. Glycogen storage diseases GSD) result from mutated genes that encode proteins involved in glycogen synthesis, degradation, and regulation. There are 14 types of glycogen storage diseases, as defined in medical records. Hers disease, or glycogen storage disease type VI (GSD VI), is an inherited condition that makes the body unable to break down glycogen in the liver cells. First described in 1959, the condition is named after Henri G. Hers, who characterized it in the said year. Failure of glycogen breakdown causes hepatic function impairment. The condition is primarily an enzymatic deficiency disorder that causes abnormal accumulation of complex sugar.

How Common Is Hers Disease?

The current estimates of Hers disease prevalence are believed to be understated owing to its indolent course. Hers disease prevalence is often recorded in combination with GSD type IX, which is basically the primary enzyme deficiency and deficiency of the enzyme regulating its activity that accounts for up to 30 percent of all glycogen storage diseases. According to research, just about 11 cases have been described in the medical literature to date. This low count may be attributed to the hidden nature of the disease. Hers disease is commonly found in the Old Order Mennonite population, with an estimated incidence of one in 1000 individuals, which is about 0.1 percent of this group. Worldwide prevalence is estimated at approximately one in 65,000 to 85,000 live births.

Hers disease shows an autosomal recessive inheritance, affecting both genders equally. The condition usually manifests during early childhood.

What Is the Cause of Hers Disease?

Owing to its inheritable nature, Hers disease has a genetic origin. Studies have found that mutations in the PYGL gene are etiologic to Hers disease. The PYGL gene encodes information required to synthesize liver glycogen phosphorylase enzymes. This enzyme is specific to the liver, where it breaks complex glycogen into simpler glucose-1-phosphate, which then gets subsequently converted to glucose. This entire cascade of events is summarized by the nomenclature-glycogenolysis, which forms glucose as per energy demand. Hepatic glycogen phosphorylase cleaves the glycosidic bonds in the glycogen molecules to produce glucose-1-phosphate. This cleaving is regulated by phosphorylase kinase, the deficiency of which causes GSD IX.

A specific splice site mutation is seen in the PYGL gene in the genomes of about three percent of the Old Order Mennonite populations. About 40 different mutations in the PYGL gene have been reported to date. The highest frequency of mutations was reported to be of the missense type. Mutated PYGL gene hampers effective glycogenolysis, which may result in a hypoglycemic state in an individual to the liver’s inability to forward glucose molecules in a state of demand. Additionally, the body may try to break down fats to meet energy needs, resulting in ketosis. Abundant glycogen accumulation can cause the hepatocytes (liver cells) to enlarge and become dysfunctional.

What Are the Clinical Features of Hers Disease?

The true prevalence of Hers disease cannot be ascertained owing to the increased frequency of no or hidden symptoms. Many of the characteristic features may only be discovered only during a routine examination or during the diagnostic steps for some other complaint.

Some of the clinical features of Hers disease include

• Protuberant abdomen.

• Growth retardation.

• Slight delay in motor milestones.

• Mild fasting hypoglycemia.

• Hepatomegaly.

• Growth retardation.

• Short stature in childhood, normal in adolescence and adulthood.

• Increased liver span with no splenomegaly.

• Mild cardiomyopathy.

• Hypoglycemia.

• Dyslipidemia (lipids imbalance).

• Ketosis.

• Bone density loss (osteopenia).

• Fragility fractures and deformities (if accompanied by osteoporosis).

• Increased glycogen in hepatocytes.

• Delayed puberty.

• Elevated hepatic transaminase (increased liver enzymes).

• Exercise-induced muscle cramps.

• Hepatic fibrosis.

• Hypotonia (low muscle tone).

• Irritability.

• Portal fibrosis.

• Post-exertional malaise.

• Sleep disturbance.

• Abnormality of the kidney.

• Cirrhosis.

• Hepatocellular carcinoma.

• Hypertrophic cardiomyopathy.

How to Diagnose Hers Disease?

• Laboratory Studies: Although it is difficult to identify Hers cases, once suspected, patients must be prescribed various laboratory procedures. Some of the parameters to study are creatinine kinase levels and fasting blood sugar levels to identify the potential fasting hypoglycemic state. Urinary analysis may reveal myoglobinuria (excess myoglobin in urine). As the liver is the primary affected organ, liver function studies are indicated, which may reveal signs of hepatic injury. Liver transaminases (SGPT-serum glutamic-pyruvic transaminase and SGOT-serum glutamic-oxaloacetic transaminase) are markedly elevated, which are potential signs of liver damage. Biochemical enzyme assay is essential to establish an astute diagnosis.

• Molecular Testing: Female patients are required to undergo molecular testing for PYGL mutations in GSD VI, whereas males are required to undergo the same in the case of GSD IX. Liver biopsy may be essential in a few handful cases. Histological studies also show rapidly progressing hepatocellular adenoma.

• Ultrasound: Liver ultrasound can be done to assess the structure and form of the liver, and bone density tests can be performed in fully grown adults.

• Tests to Differentiate: If the muscles are unaffected by GSD VI, then an ischemic forearm test may be performed to help rule out other forms of GSD. This test is expected to return negative for Hers disease. In this test, if lactate levels fail to rise with increased amounts of ammonia after strenuous activity in a cuffed forearm, it signifies a blockage of the carbohydrate metabolic pathway.

How to Treat Hers Disease?

The treatment regimen for Hers disease may be discussed under medical, surgical, and dietary heads.

1. Medical Therapy: Although there exists no cure for glycogen storage disorders, researchers have demonstrated the use of a recombinant adenoviral vector to abolish clinical manifestations of certain types of GSD in rodents. This progress suggests a possible corrective gene therapy cure for GSD (including Hers disease) in humans as well. Another successful study has provided evidence of successful enzyme replacement in mice in a certain type of GSD. This headway, as well, paves the way for future therapies in other GSD types in humans. Yet another study suggests the prescription of Clonidine as a treatment modality for Hers disease.

2. Surgical Therapy: Some advanced symptoms like hepatomegaly (liver enlargement) and hepatic adenoma (a benign liver tumor) may be surgically treated with a reduced-size liver transplant.

3. Dietary Therapy: Dietary modulation and restrictions are essential to effectively manage GSD VI symptoms. Some of the suggested means include

• Small, frequent meals instead of large, major meals.

• Uncooked cornstarch (one to two grams per kilogram body weight) between meals and before bedtime to prevent hypoglycemic states.

• Continuous overnight carbohydrate supply.

• High protein diet.

• High carbohydrate diet.

What Is the Prognosis of Hers Disease?

Most of the symptoms of Hers disease tend to improve with age with no related health conditions. According to recorded follow-ups, patients presented satisfactory post-surgical outcomes and continued to present so after four years of monitoring. It is advisable to conduct annual liver ultrasounds till the age of ten.

What Is the Differential Diagnosis of Hers Disease?

The differential diagnosis of Hers disease includes:

• Glucose intolerance.

• G6PD deficiency in the newborn.

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

• Hypoglycemia.

• Primary hepatic carcinoma.

• Type IB glycogen storage disease.

What Are the Complications of Hers Disease?

The complications of Hers disease include:

• Retarded growth.

• Hepatocellular carcinoma.

• Adenomas.

• Fragility fractures.

• Liver cirrhosis.

• Liver failure.

• Fibrotic liver.

Conclusion:

Although untreatable, Hers disease can be managed without the need for surgical interventions. Periodic fasting sugar and liver function must be monitored with blood analysis and ultrasounds to keep a close watch on any potential progression toward complications. It is also essential to continue research and studies and carry over the findings obtained from animal models and form a potential cure in humans.