HEART DAMAGE IN HEREDITARY HEMOCHROMATOSIS (CLINICAL CASE)

ABSTRACT

Hemochromatosis or (Iron-overload) is a condition in which iron excessively builds up in organs paranchemya which later cause organ toxicity and dysfunction. It is classified to 2 types. primary hereditary caused by iron regulators gene mutations, Secondary caused by thalassemia, chronic liver diseases and chronic blood transfusion. It effects organs such as skin, liver, heart, spleen, bone marrow, pituitary, pancreas and central nervous system. The present case describes hereditary hemochromatosis in a 53-years-old male patient with multi organ dysfunction and developed heart failure and the treatment plan process during the follow-up in Republican hospital №4 in Saransk. The clinical examinations involved laboratory tests, ECG, echocardiography, X-Ray and endoscopy for wide thoracic investigations.

Keywords: hemochromatosis, Heart failure, Echocardiogram, Arrhythmia.

Introduction

Hemochromatosis is a disorder in which excess iron deposits in organs tissue which later causes multiple organs dysfunction. Hemochromatosis takes place when there are high accumulation levels of non-excreted iron from the body. Hereditary hemochromatosis is the most common autosomal recessive disorder in white people. In hereditary hemochromatosis the retained iron is primarily deposited in the parenchymal cells, whereas in the case of transfusional hemochromatosis, it is primarily deposited in the reticuloendothelial cells. The excess iron is deposited in the cells as hemosiderin. This eventually leads to cell death and replacement of these cells by a fibrous deposition that causes destruction or impairment of organ function. Hereditary hemochromatosis occurs in homozygotes with a mutation of the hemochromatosis gene (HFE) protein. A mutation in the HFE gene causes increased absorption of iron despite a normal dietary iron intake. C282Y and H63D are the most common mutations of the HFE gene.[1] HFE gene is present on the short arm of chromosome 6 (6p21.3). Different types of hereditary hemochromatosis are:

1. Type 1 (HFE-related): It is the classic form of hereditary hemochromatosis that is inherited in an autosomal recessive fashion with worldwide prevalence. [2; 3]
2. Type 2a (mutations of hemojuvelin gene) and type 2b (mutations of the hepcidin gene): Autosomal recessive disorder that is seen both in whites and non-whites. Its onset is usually at 15-20 years.
3. Type 3 (mutations of transferrin receptor-2 gene): Autosomal recessive disorder that is seen both in whites and non-whites. Its onset is at 30-40 years.[4]
4. Type 4 (mutations of the ferroportin gene): Autosomal dominant disease that is seen both in whites and non-whites. Its onset is at 10-80 years.

Pathogenisis in hereditary hemochromatosis caused by mutations of genes encoding important proteins involved in iron metabolism lead to abnormal high duodenal iron absorption compared to the total body iron content. During iron overload, transferrin which is the carrier of iron in the circulation, which is normally ≈30% saturated, becomes fully saturated, due to this action, the toxic non– transferrin-bound iron species appear in the circulation. It must be emphasized that the cellular uptake of non–transferrin-bound iron is not controlled by the negative feedback mechanism that regulates transferring bound iron uptake. This, in combination with the lack of an iron excretory mechanism, leads to intracellular iron accumulation. Uptake of iron from non–transferrin-bound iron species in cardiac myocytes leads to tissue iron accumulation and, ultimately, the deleterious effects of iron overload.fig.1.

Fig.1. Iron metabolism in hemochromatosis

 In the presence of hemochromatosis, iron in the form of ferrous iron (Fe2+), enters the myocytes through the voltage-dependent L-type calcium channels. Initially iron deposition starts in the ventricular myocardium and thereafter in the atrial myocardium and effect also the conducting system.

Iron is stored in the myocytes in form of ferritin, hemosiderin, and cellular labile iron (free iron). Labile iron results in the formation of reactive oxygen species via Fenton reaction, which converts ferrous to ferric iron with the generation of the toxic hydroxyl radical. The cellular antioxidant properties are exceeded, resulting to peroxidation of membrane lipids, cellular proteins, and nucleic acids. At the same time, increased ferrous iron transportation through the L-type calcium channels also leads to derangement of cardiomyocyte calcium transportation and impaired excitation- contraction coupling, which may in turn be involved in the development of the diastolic and systolic ventricular dysfunction seen in association with iron overload.

The end result of this process is the development of a cardiomyopathy characterized mainly by LV dysfunction.fig.2.

Fig.2. Pathological process of myocardial dysfunction in Hemochromatosis

Besides direct myocardial injury, iron overload may also affect the heart indirectly through its effects on other organs such as, hepatic dysfunction, endocrinopathies (diabetes mellitus, hypothyroidism, hypoparathyroidism), and immune deficiency resulting from iron overload may contribute to the pathophysiology of IOC. Symptoms in the heart on early stages of the disease can be asymptomatic. Initial symptom are exertional dyspnea, fatigue, weakness, Restrictive/dilated cardiomyopathy, Arrhythmias, Congestive heart failure

Case Presentation

Patient J. 53 y.o. has been sick since October 2005, when after suffering from viral infection, he started to feel pain in the heart, shortness of breath and weakness, thereafter peripheral swelling and ascites developed. In November patient was urgently hospitalized in the clinical hospital of Ryazan with preliminary diagnosis Myocaditis. Hospitalization examinations results showed: Hepatosplenomegaly with signs of portal hypertension (vein expansion, Acsites), dilated cardiomyopathy with mitral and tricuspid valve insufficiency, laboratory markers showed iron overload.table1.

Table 1.

First laboratory blood test at hospital admission

ECG results showed sinus rhythm with a heart rate of 75 per minute.  Vertical position of the electrical axis of the heart.  Single ventricular extrasystoles.  Violation of metabolic processes in the myocardium.  ST segment elevation in most leads.  Three days later, QRST without dynamics.

Echocardiography: showed left atrium - 4.0 cm, thickness of the interventricular septum 1.2 cm, thickness of the posterior wall of the left ventricle 1.2 cm; EF 38%. The diastolic size of the left ventricle is 5.9 cm. Paradoxical movement of the IVS. The anteroposterior size of the right ventricle is 4.1 cm. The right atrium is significantly enlarged (6.4x5.7 cm). Vpp - 122 ml.  Compaction of papillary muscles.  Mitral valve - without features, regurgitation II degree.  Aortic valve - regurgitation of the I degree, tricuspid - III-IV degree.  Pulmonary artery - 2.8 cm. Pulmonary regurgitation of the II degree. Free fluid in the pericardium up to 150 ml. Conclusion: Dilatation of predominantly right chambers of the heart. Severe hypokinesis of the anterior wall of the right ventricle.  Signs of overload of the right ventricle, increased pressure in the right atrium. Decreased systolic function of the left ventricle.  Restrictive type diastolic dysfunction of the left ventricle. Expansion of the trunk of the pulmonary artery. Severe TC deficiency, probably relative. Relative insufficiency of mitral valve. Hydropericardium.

Ultrasound of the abdominal cavity: The liver is significantly thickened, enlarged, the edge protrudes by 7 cm. The pancreas is homogeneous, dense, the diameter of the head is 33 mm. Spleen 169x90 mm, homogeneous. Portal vein 19 mm, splenic vein 11 mm.  The gallbladder is not enlarged, the wall is thickened up to 0.4 cm, there are no stones. Kidneys of normal size, shape and position.  The pyelocaliceal system of the kidneys is not dilated.  There is about 5 liters of fluid in the abdominal cavity. There is at least 400 ml of fluid in the right pleural cavity, Hepatosplenomegaly and signs of liver cirrhosis, portal hypertension, ascites. Chronic pancreatitis. Hydrothorax on the right. X-ray of the lungs showed in the lower section on the right, a homogeneous decrease in transparency with an oblique upper border to the level of the anterior segment of the V rib. On the left, the contour of the diaphragm is blurred, the sinus is not differentiated due to fluid. The heart is enlarged, lies wide on the diaphragm. Conclusion made was hydrothorax on the right.  Fibrogastroduodenoscopy of esophagus result is freely passable. The stomach contains a moderate amount of cloudy liquid, cloudy bile. The gastric mucosa is edematous, hyperemic with submucosal hemorrhages in the upper third of the body of the stomach, we pass the gatekeeper, Bulb duodenum 12 without features. Postbulbar department is not changed. Conclusion made, Reflux esophagitis with submucosal hemorrhages in the body of the stomach.

First clinical diagnosis: Hereditary hemochromatosis. Secondary cirrhosis of the liver, portal hypertension syndrome, splenomegaly, ascites, anasarca, right-sided hydrothorax. Secondary chronic pancreatitis, secondary diabetes mellitus. Secondary metabolic cardiomyopathy, Relative insufficiency of the tricuspid valve III-IV degree, mitral valve II degree, pulmonary valve. Chronic heart failure III stage, III-IV FC.

First management was treatment carried out with virospiron, furosemide, prednisolone at a dose of 15 mg/day, asparkam, preductal. During the treatment, the patient's state of health improved significantly, abdominal pain and peripheral edema disappeared, shortness of breath decreased. On the control ultrasound of the abdominal cavity: the amount of free fluid decreased to 3 liters. Echocardiography (control) result of EF increased to 50%.

Further planned management in March 2006 planned treatment took place in hematology department in Saransk. Upon admission, the general condition of moderate severity. The skin is greyish earthy and was edema on legs is noted. Percussion sound above the lungs is dulled in the lower sections, more on the right. Vesicular breathing, sharply weakened in the lower sections, no wheezing.  The boundaries of relative cardiac dullness are extended to the left to the anterior axillary line. The heart sounds are muffled, the rhythm is correct. Heart rate - 72 per minute.  BP 110/70 mm Hg The abdomen is enlarged due to ascites.  Palpation of the liver and spleen is difficult due to ascites, percussion the liver protrudes 6 cm from under the edge of the right costal arch.  Tapping on the lumbar region is painless on both sides. In the dynamics: high levels of serum iron remained - 43.1 μmol /l .an increase in the percentage of saturation of transferrin with iron (HT) 90.1% (N 25-40%). An increase in transaminases (AlT 2.4 units / l, AST 0, 4 units/l).

On the ECG from 03.2006: Sinus rhythm with a heart rate of 70 per minute.  Vertical position of the electrical axis of the heart. Changes in the myocardium in the form of ST segment elevation in leads V1-V4, I, II, aVL, diffusely smoothed and weakly negative T waves. Hypertrophy of both ventricles. During hospitalization, hemexfusions were performed, after the next bloodletting, the patient had asystole, a state of clinical death.fig.3.

Fig. 3. State of clinical death on ECG after bloodletting during hospitalization

After the ongoing resuscitation, the heart rhythm was restored according to the type of atrial flutter.The patient then transferred to the intensive care unit, where sinus rhythm was restored against the background of antiarrhythmic drugs, after which he received cordarone under the control of ECG and ECG-HM.fig.4.

Fig. 4. Heart rhythm restored according to the atrial flutter

DNA diagnostics done on March 23, 2006

Results showed mutations in the HFE hemochromatosis gene: C282Y - normal, S65C - normal, H63D (heterozygous).

On October 2008 examined in Moscow (Hematological Research Center). A clinical diagnosis was made: Hereditary hemochromatosis (not type I C282Y-/-, H63D+/-, S65C-/-) with damage to the liver and heart. Cirrhosis of the liver (stage A according to Child-Pugh). Restrictive cardiomyopathy. Heart failure II  (NYHA). Violation of the heart rhythm according to the type of frequent ventricular extrasystole, paroxysms of ventricular tachycardia (IV B gradation of Laun). Paroxysmal form of atrial fibrillation. Condition after asystole and resuscitation (dated March 22, 2006). Hereditary thrombophilia (mutation of the prothrombin gene). Complete blood count is normal.

Iron metabolism showed increased levels of iron.table.2.

Table 2.

Iron overload markers

Urinary excretion of metals before treatment with chelators: total daily urine 2.4 l, iron 21.1 copper 23.5 zinc 17.3 Metal excretion in urine after desferal: total daily urine 2.5 l, iron 373.0 copper 42.0 zinc 137 Test for markers of hemochromatosis.

In 15.10.2008, Liver biopsy with biochemical and immunohistochemical examination of liver tissue, in the liver biopsy revealed a significant expansion of the zones of the portal tracts due to fibrosis, slight proliferation of the ducts and massive lymphohistiocytic infiltration. Hepatocytes show anisocytosis, signs of dystrophy with massive deposits in their cytoplasm and hemosiderin Kupffer cells.  The presence of hemosiderin was confirmed by the Perls test.

Conclusion: in the liver biopsy, there is a picture of active (pigmented) cirrhosis.

Viral hepatitis markers showed  (DNA-HBV, RNA-HCV negative). Liver biopsy for minerals: iron 120.3, copper 17.8, zinc 73.7, ferritin 7077.3, hepcidin 1339, HIF 150.

Ultrasound of the abdominal cavity: liver, left lobe 151x60mm, right lobe 214x138mm. The contours are even, the structure with pronounced diffuse changes, the echogenicity is increased. Portal vein 16mm.  Splenic vein 10mm. Spleen 158x62mm. EchoCS: left ventricular hypertrophy of mixed type.  Increased echogenicity of the myocardium of the left ventricle. Tricuspid regurgitation stage 2-3. Mitral regurgitation 1-2 stage. Type 2 LV diastolic dysfunction. The contractility of the myocardium is not sharply reduced.

Treatment:

2005-2006 - plasmapheresis and hemexfusion sessions

2006-2007 - courses of chelation therapy Desferal 1000 mg/day IV 8 infusions (cancellation due to the development of toxic-allergic dermatitis on the drug).

 From 2008-2016 - chelation therapy deferasirox (Exjade) 1000 mg/day orally.

Symptomatic therapy: Cordarone 200 mg/day - 5 days a week, Ursofalk 500 mg/day, antisecretory therapy.  Antioxidant courses (mexidol, emoxipin),

Metabolic therapy (IV Cernevit, IV Medivitan, Folic acid 2 mg/day).

After 8 years of chelation therapy, there is a positive trend: in the form of a decrease in skin pigmentation and a regression in the size of the liver and spleen (according to the control ultrasound, the liver protrudes 2 cm from under the edge of the costal arch, the spleen is 146x57 cm),

 laboratory picture of iron deficiency (a decrease in serum  iron up to 25.2 µmol/l and saturation of transferrin with iron (HT) - up to 44%).

According to the control EchoCS - improvement in myocardial contractility, tricuspid regurgitation decreased to 1-2st, mitral regurgitation 1st.

MRI of the liver and heart revealed no iron overload.

Chelation therapy was cancelled.  Continued antiarrhythmic therapy Cordarone and Perindopril.

After 15 month break in chelation therapy, there is no laboratory picture of iron overload, but according to MRI, liver with iron overload. There is a negative cardiological dynamics (more frequent attacks of interruptions in the work of the heart and palpitations).

Holter ECG monitoring: the appearance of a paired ventricular extrasystole increase in the PVC with IV according to Laun-Wolf classification.  The arrhythmia is stratified as "malignant" according to Bigger classification (given a history of cardiac arrest). EchoCS - negative dynamics: an increase in the chambers of the heart (both atria and left ventricle) with hypertrophy of the walls of the left ventricle, clinically significant tricuspid regurgitation grade 3.

Final diagnostic report: Hereditary hemochromatosis (not type I C282Y-/-, H63D+/-, S65C-/-) with damage to the liver and heart. Cirrhosis of the liver (stage A according to Child-Pugh). Cardiomyopathy: arrhythmic form (malignant arrhythmia according to Bigger).  Ventricular extrasystole of high gradations according to Laun-Wolf (IV B gradation Lawn). Paroxysmal tachysystolic form of atrial fibrillation.  Condition after asystole (dated March 22, 2006).  NK II (NYHA). Hereditary thrombophilia (mutation of the prothrombin gene).

Correction of antiarrhythmic therapy: escalation of the dosage and frequency of taking Cordarone 300 mg / day daily; Perindopril 2.5 mg/day, Verospiron 25 mg/day. After 1 month of this therapy, according to ECG, positive results in the form of a reduction in the number of PVCs, the absence of paired ES, the absence of early ES.

from 10/14/2019. MRI was done to determine the iron content in the liver and heart signs of mild liver iron overload.  Iron overload of the heart was not detected.  Decrease in Laun class from IV to II.  Episodes of allorhythmia and a tendency to lengthening of AV conduction are persist. The dose of cordarone was reduced to 200 mg/day – 5 days a week. Chelation therapy Deferasirox (Exjade) has been resumed since 2020, 1000mg/day.

In 24.11.2022 serum iron test was done.table.4.

Table 4.

High serum iron levels

In 28.11.2022 Ultrasound signs showed hepatomegaly on the right lobe, splenomegaly, minor diffuse changes in liver parenchyma, chronic cholecystitis, echogenic bile in the gallbladder, structural changes in the pancreas on type of chronic pancreatitis, thickening of pelvicalyceal system of both kidneys.

In 30.11.2022 Echocardiography showed thickening of aortic walls, Aortic valve regurgitation- 1 degree. Mitral valve regurgitation 1-2 degree.

Slight hypertrophy of intraventricular septum, Diastolic LV dysfunction of I type. A small dilatation of the left chambers of the heart and right atrium. Hypokinesis of the anterior segment of LV at the high level. The general contractility of LV has been reduced. Tricuspid regurgitation- 2 degree.

Slight pulmonary hypertension (PASP,СДЛА - 34mm Hg).Thyroid ultrasound was done to exclude Thyroid changes due to side effect of Cordarone.fig.1.[5]

Fig. 5. 1.Aortic regurgitation 1degree. 2.Mitral valve regurgitation 1-2degree. 3.slightly hypertrophy of IVseptum. 4.dilation of left chamber

Fig.5. 5.tricuspid regurgitation 2degree. 6.thyroid ultrasound excluded pathology changes

Conclusion:

The diagnosis of hereditary hemochromatosis was confirmed by the results of immunohistochemical examination of liver tissue, detection of the genetic marker HFE H63D+ (heterozygous inheritance), laboratory signs of iron overload.

Heart damage in hereditary hemochromatosis is manifested by the early development of dilated cardiomyopathy with mitral and tricuspid valve insufficiency, followed by arrhythmic cardiomyopathy with diastolic myocardial dysfunction.

Against the background of Chelation therapy for 8 years and taking cordarone - normalization of contractility and diastolic function of the myocardium, absence of paroxysms of atrial fibrillation, reduction of the class of ventricular extrasystoles according to Lohn-Wolf to class II.