;

1. Investigator : Dr. Henock Hailu
Advisor : Dr. Sewagegn (pediatrician and Endocrinologist)

2. Outline
1. Tile of the research
2. Background of the study
3. Statement of the problem and significance of the study
4. Objectives of the study
5. Literature review
6. Conceptual Framework
7. Methods
8. Operational definition

3. Title
Prevalence ,Risk Factor and commonest site of lipodystrophy
among Type 1 Diabetic Patients taking Subcutaneous Insulin on
follow up at Black Lion Hospital Pediatric Endocrinlogy Unit ,
Addis Ababa, Ethiopia

4.  Lipodystrophy (LD), a disorder of adipose tissue, is one of the most common
complications of subcutaneous insulin injections and may present as either
lipohypertrophy (LH) or lipoatrophy (LA).
 The latter is defined as a large, often deep, retracted scar on the skin that results
from serious damage to subcutaneous fatty tissue [1].
 Several features of LA suggest an immunological etiology [2]: (1)
 it is more frequent in patients with type 1 diabetes, and mostly affects women—who
often have other signs of autoimmunity; it is often characterized by the presence of
mast cells and eosinophils in biopsy specimens
 it seems to be the result of a lipolytic reaction to impurities or other components in
some insulin preparations, as its prevalence has dropped to only 1–2% with the
increasing use of purified insulin

5.  LH is a thickened ‘rubbery’ tissue swelling which is mostly firm but may
occasionally present as a soft lesion as well, and thus it is easily missed during a
standard medical examination. Although the exact etiology of LH is unclear, several
local factors appear to be at play, including both the insulin molecule per se—with
its strong growth-promoting properties—and repeated trauma caused by poor
injection habits, such as infrequent/missed injection site rotation and/or frequent
needle reuse [1]. However, a large body of evidence also lends support to a
significant association between LH and many other factors, including female sex,
low socioeconomic level, high body mass index, as well as long-standing disease
and/or insulin treatment. LH lesions are generally correctly identified during the
course of any accurate examination, although in various published series the steps
taken to do so were not fully documented

6.  A missed diagnosis of LD may have major clinical consequences. The
injection of insulin into parts of the body affected by LD may cause wide
glycemic oscillations, including inappropriately high glucose levels and a
high rate of unexplained hypoglycemic episodes, both of which are
scarcely responsive even large changes in insulin dose [1, 8]. Programs
aimed specifically at educating patients with LD on proper injection
techniques has proven to be effective in significantly reducing glucose
oscillations [9].
 Despite LH and LA on occasion being used improperly as synonyms [3],
we suggest that the two concepts be kept separate.

7.  Most studies suggest that insulin absorption at areas affected by LH may be both delayed and erratic,
leading to the need for ever increasing doses of insulin and worsening metabolic control [10–14]. This in
turn causes unacceptable glucose oscillations due to a high rate of serious hypoglycemic episodes followed
by rebound glucose spikes whenever patients suddenly switch from affected injection sites to normal ones.
Under these conditions, the economic burden of the disease increases for both patients and the healthcare
system. Therefore, it is crucial that as many areas affected by LH as possible are systematically identified in
order to educate patients on good insulin injection habits. The reported prevalence of LH in patients
receiving insulin injections varies widely in published studies [6], possibly due to the lack of a well-
structured diagnostic flow-chart despite the world-wide availability of suitable ultrasound and radiological
methods [1, 15–24]. We recently published a methodological paper on a palpation technique that enables
the clinician to identify skin lipohypertrophic lesions in diabetic patients receiving insulin [6]. We
therefore propose that diabetes teams be formed at medical institutions which would systematically follow
that simple procedure we describe for the diagnosis of LH at all insulin injection sites and then implement
and hopefully progressively refine this procedure in large-scale studies. In particular, unexplained
variations in glucose levels and/or unexplained hypoglycemic episodes may alert healthcare providers to
look for LH in diabetic patients receiving insulin injections.

8.  Lipodystrophy syndromes are a heterogeneous group of diseases, characterized by
selective absence of adipose tissue. In one sense, these diseases are lipid-
partitioning disorders, where the primary defect is the loss of functional adipocytes,
leading to ectopic steatosis, severe dyslipidemia and insulin resistance. These
syndromes have attracted significant attention since the mid-1990s as the
understanding of adipose tissue biology grew, initially spurred by the discovery of
the pathways leading to adipocyte differentiation and maturation, and then by the
discovery of leptin. Although lipodystrophy syndromes are known since the
beginning of the 20th century, significant progress in understanding these
syndromes were made in the last two decades, placing these syndromes at the
forefront of the translational metabolism field. Currently, more than 15 distinctive
molecular etiologies have been attributed to cause human diseases most of which
map to adipocyte differentiation or lipid droplet pathways. Seemingly acquired
syndromes are recently reported to have a genetic basis, suggesting that our “pre-
genome” understanding of the syndromes was inadequate and that we need to
likely change our classification schemes.

9.  Regardless of the etiology, it is the selective absence of adipose tissue and the
reduced ability to store long-term energy that perturbs insulin sensitivity and lipid
metabolism. The treatment of these syndromes has also attracted considerable
interest. The most successful example of the treatment of these syndromes came
from the demonstration that leptin replacement strategy improved insulin
resistance and dyslipidemia in the most severely affected forms of the disease,
leading to an FDA approved therapy for generalized lipodystrophy syndromes. In
the partial forms of the disease, the phenotypes are more complex and the efficacy
of leptin is not as uniform. Currently, numerous trials are in progress for the
development of potential new treatments for the partial forms of the disease. These
rare metabolic diseases are likely to fuel novel breakthroughs in the metabolism
field in the foreseeable future. For complete coverage of all related areas of
Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

11.  1Consequences of Lipodystrophy: The figure summarizes metabolic
derangements and end-organ complications in patients with
lipodystrophy (Left: MRI showing near total lack of adipose tissue; Right
top: Liver biopsy shows hepatic steatosis in lipodystrophy (Hematoxylin
and eosin staining; magnification 100X), Right bottom: CT of abdomen
obtained during an episode of acute pancreatitis in lipodystrophy; Middle
top: Diabetic foot ulcer in a patient with generalized lipodystrophy;
Middle bottom: Renal biopsy specimens (Left: Electron microscopy image
reveals lipid vacuoles which suggest ectopic lipid accumulation

12.  Lipodystrophy syndromes comprise a heterogeneous group of disorders
characterized by either generalized or partial lack of adipose tissue depending on
the type of lipodystrophy 1,2. Lipodystrophy classically has been classified as
congenital or acquired. Patients with partial lipodystrophy may exhibit excess
adipose tissue accumulation in other areas of the body. Lipodystrophy syndromes
usually manifest with several metabolic abnormalities associated with severe insulin
resistance that include diabetes mellitus, hypertriglyceridemia, and hepatic
steatosis which can progress to steatohepatitis. Other common manifestations are
acanthosis nigricans, polycystic ovarian syndrome (PCOS), and eruptive xanthomas
(due to severe hypertriglyceridemia) 3,4. Metabolic derangements are mostly
responsible for the serious comorbidities associated with lipodystrophy; some of
which are chronic complications of poorly controlled diabetes, acute pancreatitis,
hepatic cirrhosis, proteinuria and renal failure, and premature cardiovascular
disease (Fig.1) 1,2.

13.  Typically, standard treatments fail to achieve good glycemic control in
most patients with lipodystrophy, although episodes of diabetic
ketoacidosis have been rarely reported5. The severity of the comorbidities
depends on the subtype, extent of fat loss, and other clinical
characteristics such as gender and age. Major causes of mortality are
cardiovascular diseases 6-9, liver diseases2,10, acute pancreatitis 2, renal
failure 10, and sepsis 3. Clinical characteristics of lipodystrophy are shown
in Table 1. It is important to note that there are additional components of
the disease that may be specific to each molecular etiology. In addition,
we are beginning to recognize that patients often report reduced quality of
life with increased overall pain (requiring frequent use of pain
medications), sleep disturbances and sleep apnea, gastrointestinal
dysmotility, mood disturbances such as depression and anxiety and
psychiatric diseases 11,

14.  Metabolic abnormalities
 · Relatively early onset of insulin resistant diabetes which is severe in some patients
with requirement for high doses of insulin, e.g., requiring ≥200 U/day, ≥2 U/kg/day,
or U-500 insulin, early development of complications
 · Dyslipidemia which is characterized by elevated triglycerides and low HDL
cholesterol. Hypertriglyceridemia can be very severe (≥500 mg/dL) and is
unresponsive to treatment with associated history of acute pancreatitis
 · Hepatomegaly and/or elevated transaminases in the absence of a known cause of
liver disease (e.g., viral hepatitis). Hepatic steatosis (e.g. radiologic evidence),
Hepatomegaly, non-alcoholic steatohepatitis (NASH), cirrhosis.

15.  Lipodystrophy is an exciting rare disease that helps us obtain a better understanding of the
pathophysiology of metabolic abnormalities associated with insulin resistance. The main cause of insulin
resistance in lipodystrophy is the fact that the excess energy cannot be stored in adipose tissue, which is
secondary to either the near total lack of adipocyte expandability in patients with generalized
lipodystrophy or a limited capacity to expand in partial lipodystrophy. Limited lipid storage capacity causes
the failure of buffering postprandial lipids and secreting substantial adipokines, which in turn results in
excessive levels of triglycerides and lipid intermediates in circulation. The body stores fat at ectopic sites
such as the liver as a result of inability to store energy in the subcutaneous adipose depots (Fig.1). Levels of
adipokines and hormones secreted from the adipose tissue, most characteristically leptin, are decreased in
these patients 1,2,9,13,14. Leptin has a fundamental role in glucose and lipid homeostasis. Leptin is the key
hormone responsible for regulating appetite 15. Low levels of leptin in lipodystrophy trigger hyperphagia,
which is often extreme 16-18. Leptin protects pancreatic beta cells from lipotoxicity at least in rodent
models. Leptin improves insulin sensitivity by increasing glucose uptake in peripheral tissues such as
muscle via sympathetic nervous system activation. Leptin also decreases hepatic gluconeogenesis

18. Background of the study
Bronchopulmonary dysplasia (BPD)
 First described by Northway and colleagues in 1967 as a lung injury in preterm infants
resulting from oxygen and MV.
 Important cause of respiratory illness in preterm that results significant mortality and
morbidity.
 The strongest risk factor are low birth weight and prematurity.
 Common complication of prematurity and increase prevalence, most likely due to the
increased survival of ELGANs .

19. Statement of the problem
 The incidence and associated risk factor of BPD is not known in Ethiopia and
most Africa Country
 There is huge knowledge gap in Ethiopia
 Recently BPD emerging problem for low income country due to increased
preterm survival.

20. Significance of the study
 Addresses important knowledge gap:
 Incidence in the country's largest health care institutions
 Risk factors associated with BPD
 Impact of Research on practice:
 Exposure to a largely overlooked and emerging problem
 Allocation of health system resources
 Inform policy changes

21. Objective of the study
 General Objective
 To measure the incidence and associated risk factor of BPD among preterm neonates
admitted to Tikur Anbessa specialized teaching hospital and St Paul’s specialized teaching
hospital in the study period.
 Specific ojective
 To measure incidence of BPD among preterm neonate
 To describes associated risk factor of BPD among preterm neonate
 To compare proportion of early and late preterm neonates who had BPD

22. Literature review
 The incidence of BPD varies widely between centers(~20–75%),due to:
 differences in gestational age or birth weight criteria for a BPD diagnosis,
 advanced neonatal care.
 Study in South Africa, review of neonatal chronic lung disease (CLD), over all
incidence of CLD was 5%.
 Study in India in 2017, on prevalence of BPD, over all incidence was 11.2%
 Strongest risk factors for BPD are prematurity and low birth weight
 Perinatal risk factors IUGR, male sex, chorchorioamnionits, race or
ethnicity, maternal smoking and genetic risk.

23. Low birth
weight
Prematurity
Male sex
Maternal smoking
BPD
chorioamnionitis
Mechanical
ventilator
Lung/systemic
infection
Necrotizing
enterocolitis
Intrauterine grow
retardation(IUGR)
Conceptual framework

24. Method
Study setting and period
 Study will be conducted at St. Paul's specialized teaching hospital and Tikur
Anbessa specialized teaching hospital NICU over the last 2 year, Addis Ababa,
Ethiopia.
Study design
 Retrospective cohort study

25. Method
Source population
 All preterm neonate admitted at Tikur Anbessa specialized hospital and St.
Paul's specialized teaching hospital NICU for the last 2year.
Study population
 All preterm neonate admitted at Tikur Anbessa specialized teaching and St.
Paul's specialized hospital NICU who had BPD for the last 2 year.

26. Method
 Inclusion Criteria
 Gestational age less than 37 weeks
 Admitted at Tikur Anbessa and St Paul’s
Hospitals
 Both in born and out born admitted
<7days
 Previous 2 year
 Exclusion Criteria
 Cyanotic CHD
 congenital lung/ airway
malformations
 other lethal congenital
diseases
Eligibility criteria

27. Method
Accessing all folders of
preterm neonates in the
last 2 years
Ineligible
Lost folders
Folders with
missing
essential data*
folders fulfilling
the exclusion
criteria
Eligible

28. Method
Sample Size
 The total sample was determine
 95% CI and 5% margin of error
 P= 5% (previous research in south Africa)
 n=88
 Calculations performed using epitools Sample Size for Independent Cohort Studies

29. Method
Data collection methods
 Retrospectively data will be collected from chart by proper check list starting from most
recent
 Data collectors will be trained on the data collection tools.
Data analysis
 Data entry, cleansing and analysis will be done using SPSS.
 Binary logistic regressions will be used to analyse the relationship b/n the dependent and
independent variables.
 Association will be done using odds ratio; P value < 0.05 will be considered statistically
significant

30. Operational defination
 BPD - the continued need for oxygen support at:
 Postnatal age of 28 days Corrected gestational age of 36 weeks
(whichever comes first)
Outcome
BPD
yes No
Exposu
re
GA
<32 weeks
Very/extremely
Preterm with BPD
Very/extremely
without BPD
32-37 weeks
Moderate/late
preterm with BPD
Moderate/late
preterm without
BPD

31. Reference
1. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane
disease: bronchopulmonary dysplasia.N Engl J Med1967;276:357–368.
2. Stoll, B. J. et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network.
Pediatrics 126, 443–456 (2010).
3. Mphaphuli A V, Ballot D E. A review of chronic lung disease in neonates at Charlotte Maxeke Johannesburg
Academic Hospital from 1 January 2013 to 31 December 2014. S. Afr. j. child health [Internet]. 2016 Sep
[cited 2022 Oct 25] ; 10( 3 ): 161-165. Available from:
http://www.scielo.org.za/scielo.php?script=sci_arttext&pid=S1999-
76712016000300005&lng=en. http://dx.doi.org/10.7196/sajch.2016.v10i3.1060.
4. Siffel C, Kistler KD, Lewis JFM, Sarda SP. Global incidence of bronchopulmonary dysplasia among extremely
preterm infants: a systematic literature review. J Matern Fetal Neonatal Med. 2021 Jun;34(11):1721-1731. doi:
10.1080/14767058.2019.1646240. Epub 2019 Aug 9. PMID: 31397199.
5. Bose, C. et al. Fetal growth restriction and chronic lung disease among infants born before the 28th week of
gestation. Pediatrics 124, e450–e458 (2009).
6. Morrow, L. A. et al. Antenatal determinants of bronchopulmonary dysplasia and late respiratory disease in
preterm infants. Am. J. Respir. Crit. Care Med. 196, 364–374 (2017)
7. Hartling, L., Liang, Y. & Lacaze-Masmonteil, T. Chorioamnionitis as a risk factor for bronchopulmonary
dysplasia: a systematic review and meta-analysis.Arch. Dis. Child Fetal. Neonatal Ed. 97, F8–F17(2012).

32. Thank you!